Nonsteroidal antiinflammatory agents

ABSTRACT

The compound of formula 1  
                 
 
     useful in the treatment of inflammation.

[0001] This invention relates to the use of nonsteroidal compounds forthe production of pharmaceutical agents for treatment of inflammations,selected compounds and production processes thereof.

[0002] In addition to a large number of steroid compounds, which bindwell to the glucocorticoid receptor and have an antiinflammatory action(glucocorticoids), nonsteroidal compounds are known that namely bind tothe glucocorticoid receptor, for which to date no antiinflammatoryaction has been shown, however [cf. Nature Medicin 4 (1998) 92, Mol.Pharmacol. 52 (1997) 571]. In addition, nonsteroidal compounds weredescribed that are derived from steroidal compounds, have an affinity tothe glucocorticoid receptor and probably have an antiinflammatory actionthat is mediated by the receptor [J. Med. Chem. 36, (1993), 3278-3285].In animal experiments, however, these compounds did not show anyadvantages relative to steroidal glucocorticoids, i.e., it was notpossible to separate the antiinflammatory action from the metaboliceffects, e.g., suppression of the suprarenal function.

[0003] From WO 98/54159, nonsteroidal compounds are known that have ahigh gestagenic activity. In the document, there is the observation thatthe claimed compounds partially also have action on the glucocorticoidand/or mineral corticoid receptor. In this connection, however, there isneither actual mention of compounds nor disclosure of test results. Thatis to say that from the pool of generically claimed compounds of WO98/54159, compounds that are not specified in more detail are known thathave both high gestagenic activity and action on the glucocorticoidreceptor. In terms of industrial applicability, however, compounds thathave a selectivity with respect to the above-mentioned actions areadvantageous.

[0004] In turn, from WO 00/32584, phenol derivatives that have adissociation of action between antiinflammatory action and undesirablemetabolic side effects are known as nonsteroidal antiinflammatoryagents.

[0005] The compounds that are disclosed in the prior art are still inneed of improvement with respect to their dissociation of action betweenantiinflammatory action and the undesirable side effects.

[0006] The object was therefore to make available new nonsteroidalantiinflammatory agents that show a dissociation of action that is atleast as good or better than the compounds of the prior art.

[0007] Nonsteroidal compounds have now been found that bind well to theglucocorticoid receptor and, mediated by this bond, produce anantiinflammatory action. In the experiment, these compounds show asignificantly better or at least equally good dissociation of actionbetween antiinflammatory and undesirable actions and are superior to thepreviously described nonsteroidal glucocorticoids or have at least justas good an action.

[0008] According to this invention, the following compounds of generalformula I that have an antiinflammatory action are suitable for use forthe production of pharmaceutical agents:

[0009] in which

[0010] R¹ and R² are the same or different and stand for a hydrogenatom, a C₁-C₅ alkyl group, or, together with the C-atom of the chain,stand for a ring with a total of 3-7 links,

[0011] R³ stands for a straight-chain or branched C₁-C₅ alkyl group or astraight-chain or branched, partially or completely fluorinated C₁-C₅alkyl group,

[0012] A stands for the group

[0013]  (the dashed line means the interface site), in which

[0014] R⁴ to R⁸ are the same or different from one another and mean ahydrogen atom, a halogen atom, a cyano group, a nitro group, a COOR⁹group

[0015] whereby R⁹ stands for a hydrogen atom, a straight-chain orbranched C₁-C₅ alkyl group or a benzyl group,

[0016] a CONR¹⁰ group,

[0017] whereby R¹⁰ stands for a hydrogen atom or a straight-chain orbranched C₁-C₅ alkyl group,

[0018] an NHR¹¹ group,

[0019] whereby R¹¹ stands for a hydrogen atom, a straight-chain orbranched C₁-C₅ alkyl group, a straight-chain or branched, partially orcompletely fluorinated C₁-C₅ alkyl group, a C₁-C₅ acyl group, an—SO₂—(C₁-C₅) alkyl group or an —SO₂-phenyl group that is optionallysubstituted by halogen or a C₁-C₅ alkyl group,

[0020] a straight-chain or branched C₁-C₅ alkyl group, a straight-chainor branched C₂-C₅ alkenyl group, a straight-chain or branched C₂-C₅alkinyl group, a straight-chain or branched C₁-C₅ alkyl group that ispartially or completely substituted by fluorine atoms, a C₁-C₅ acylgroup, an aryl radical or a heteroaryl radical,

[0021] R⁴ and R⁵ together with the two carbon atoms of ring A mean asaturated or unsaturated carbocyclic ring with a total of 5-7 links,

[0022] Ar stands for a ring system, selected from the group of generalpartial formula 1 or 2,

[0023]  in which

[0024] radicals x^(3a), X^(3b), X⁴, X⁶, X⁷ (in partial formula 1) andY⁴, Y⁵, Y⁷, and Y⁸ (in partial formula 2) are the same or different andmean a hydrogen atom, a straight-chain or branched C₁-C₅ alkyl group, ora straight-chain or branched, partially or completely fluorinated C₁-C₅alkyl group,

[0025] radicals X⁴, X⁶, X⁷ (in partial formula 1) or Y⁵, Y⁷, Y⁸ (inpartial formula 2) in addition are the same or different and mean ahydrogen atom, a halogen atom, a hydroxy group, a C₁-C₅ alkoxy group ora C₁-C₅ alkanoyloxy group,

[0026] as well as their racemates or separately present stereoisomers,and optionally their physiologically compatible salts.

[0027] The compounds of general formula I according to the invention canbe present as different stereoisomers because of the presence ofasymmetry centers. Both the racemates and the separately presentstereoisomers are part of the subject matter of this invention.

[0028] A special subject of this invention are the isomers that turn theplane of polarized light in the way that they are referred to as(+)-compounds.

[0029] The substituents that are defined as groups or radicals in thecompounds of general formula I can have the meanings below in each case.

[0030] The C₁-C₅ alkyl groups R¹, R², R³, R⁴, R⁵, R¹², X^(n), and Y^(o)can be straight-chain or branched and can stand for a methyl-, ethyl-,n-propyl-, iso-propyl-, n-butyl, iso-butyl, tert-butyl or n-pentyl,2,2-dimethylpropyl-, 2-methylbutyl- or 3-methylbutyl group. A methylgroup or ethyl group is preferred.

[0031] If R¹ and R² together with the C-atom of the chain form a 3- to7-membered ring, the latter optionally can be substituted by 1-2 oxygenatoms and can be, for example, a cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl or cycloheptyl ring.

[0032] For a partially or completely fluorinated C₁-C₅ alkyl group, thepartially or completely fluorinated alkyl groups that appear above areconsidered. Of the latter, the trifluoromethyl group or pentafluoroethylgroup, as well as partially fluorinated alkyl groups, for example the5,5,5,4,4-pentafluoropentyl group or 5,5,5,4,4,3,3-heptafluoropentylgroup, are preferred. The trifluoromethyl group and the pentafluoroethylgroup are preferred.

[0033] The substituents of phenyl ring A, independently of one another,can have the meanings that are defined in the claims, such as a hydrogenatom, a halogen atom, a cyano group, a nitro group, an NHR¹¹ group,whereby R¹¹ stands for a hydrogen atom, a straight-chain or branchedC₁-C₅ alkyl group, a straight-chain or branched, partially or completelyfluorinated C₁-C₅ alkyl group, a C₁-C₅ acyl group, an —SO₂—(C₁-C₅)alkylgroup or an —SO₂-phenyl group that is optionally substituted by halogenor a C₁-C₅ alkyl group, a straight-chain or branched C₁-C₅ alkyl group,a straight-chain or branched C₂-C₅ alkenyl group, a straight-chain orbranched C₂-C₅ alkinyl group, a straight-chain or branched C₁-C₅ alkylgroup that is partially or completely substituted by fluorine atoms, aC₁-C₅ acyl group, an aryl radical or a heteroaryl radical.

[0034] Preferred are phenyl rings A, which carry 1-3 non-hydrogensubstituents.

[0035] In addition, R⁴ and R⁵ together with the two carbon atoms of ringA can mean a saturated or unsaturated carbocyclic ring with a total of 5to 7 links, such as, for example, indane, naphthalene,tetrahydronaphthalene, benzocycloheptane.

[0036] A subject of the invention is the use of the compounds of generalformula I in which R⁴ to R⁸ are the same or different from one anotherand mean a hydrogen atom, a halogen atom, a cyano group, a nitro group,a COOR⁹ group, whereby R⁹ stands for a hydrogen atom, a straight-chainor branched C₁-C₅ alkyl group or a benzyl group, a CONR¹⁰ group, wherebyR¹⁰ stands for a hydrogen atom or a straight-chain or branched C₁-C₅alkyl group, an NHR¹¹ group, whereby R¹¹ stands for a hydrogen atom, astraight-chain or branched C₁-C₅ alkyl group, a straight-chain orbranched, partially or completely fluorinated C₁-C₅ alkyl group, a C₁-C₅acyl group, a —SO₂—(C₁-C₅)alkyl group or an —SO₂-phenyl group that isoptionally substituted by halogen or a C₁-C₅ alkyl group, astraight-chain or branched C₁-C₅ alkyl group, a straight-chain orbranched C₂-C₅ alkenyl group, a straight-chain or branched C₂-C₅ alkinylgroup, a straight-chain or branched C₁-C₅ alkyl group that is partiallyor completely substituted by fluorine atoms, a C₁-C₅ acyl group, an arylradical or a heteroaryl radical.

[0037] The designation halogen atom or halogen means a fluorine,chlorine, bromine or iodine atom. Preferred is a fluorine, chlorine orbromine atom.

[0038] For a C₂-C₅ alkenyl group, for example, a vinyl, 2-substitutedvinyl group, 1-propenyl, 2-propenyl, 2- or 3-substituted 2-propenylgroup, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl,2-methyl-2-propenyl, 1-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl,and 3-methyl-1-butenyl group are considered. Preferred are the alkenylgroups, which carry the double bond in 1- or 2-position. As substituentsfor the vinyl group or the propenyl group, primarily the methyl group orthe ethyl group is suitable.

[0039] A C₂-C₅ alkinyl group is defined as, for example, an ethinyl,1-propinyl, 2-propinyl, 1-butinyl, 2-butinyl, 3-methyl-1-butinyl,4-methyl-1-butinyl or 1-pentinyl group. Preferred are the alkinyl groupsthat carry a triple bond in 1-position or 2-position.

[0040] With the C₁-C₅ acyl group, for example, a formyl, acetyl,propionyl, n-butyroyl, 2-methylpropionyl, n-valeroyl, 2-methylbutyroyl,3-methylbutyroyl or a pivaloyl group is meant.

[0041] With a sulfonyl(C₁-C₅) alkyl group R¹¹, for example, amethylsulfonyl group or an ethylsulfonyl group is meant.

[0042] For the sulfonylphenyl group R¹¹ that is optionally substitutedby halogen or a C₁-C₅ alkyl group, 2-chloro(phenylsulfonyl),3-chloro(phenylsulfonyl), 4-chloro(phenylsulfonyl),2-methyl(phenylsulfonyl), 3-methyl(phenylsulfonyl), and4-methyl(phenylsulfonyl) can be mentioned. The sulfonyl group is bondedwith its free valency to the nitrogen atom of the NHR¹¹ group.

[0043] Aryl means a phenyl group or a substituted phenyl group.

[0044] As substituents of the aryl group, halogen atoms, the cyano,nitro, C₁-C₅ alkoxy, amino, hydroxy, carboxy and C₁-C₅ alkanoyl groups,branched and unbranched C₁-C₅ alkyl groups, branched and unbranchedC₁-C₅ alkyl groups, which can be partially or completely fluorinated,are suitable.

[0045] Heteroaryl comprises aromatic heterocyclic 5- and 6-rings, whichcan contain in the ring 1-3 additional heteroatoms from the group ofoxygen, nitrogen or sulfur. Preferred are heterocyclic five-memberedrings. In particular, furyl, thienyl, pyridyl, thiazolyl, oxazolyl,oxadiazolyl, and imidazolyl can be mentioned.

[0046] The heteroaryl groups optionally can be substituted by branchedand unbranched C₁-C₅ alkyl groups, branched and unbranched C₁-C₅ alkylgroups that can be fluorinated and/or halogen atoms.

[0047] The hydroxy groups that are possible for radicals X^(n), Y^(o)can optionally be defined below as ethers or esters:

[0048] As a C₁-C₅ alkyl group for etherification of hydroxy groups, theabove-mentioned alkyl groups are suitable, especially a methyl group orethyl group.

[0049] As a C₁-C₅ alkanoyl group for esterification of hydroxy groups, aformyl, acetyl, propionyl, butyryl, iso-butyryl, valeryl or iso-valerylor pivaloyl group is considered, preferably an acetyl group.

[0050] As a C₁-C₅ acyl group for esterification of hydroxy groups, forexample, the above-mentioned alkanoyl groups, preferably in turn anacetyl group, or a benzoyl, toluoyl, phenylacetyl, acryloyl, cinnamoylor cyclohexylcarbonyl group, can be mentioned.

[0051] As a C₁-C₅ alkanoyloxy group for X⁴, X⁶, X⁷, Y⁴, Y⁵, Y⁷ or Y⁸, aformyloxy, acetoxy, propionyloxy, butyryloxy, iso-butyryloxy, valeryloxyor iso-valeryloxy group is considered, preferably an acetoxy group.

[0052] Preferred are compounds in which Ar stands for partial formula 2,and Y⁴ means a methyl group.

[0053] Especially preferred are compounds in which Ar stands for partialformula 2, Y⁴ means a methyl group, and the other substituents Y⁵, Y⁷and Y⁸ mean hydrogen.

[0054] Nonsteroidal compounds as such with a mixed profile that consistsof gestagenic and androgenic activity in different manifestations arealready the subject of WO 98/54159. The compounds of general formula Iaccording to claim 1 that are to be used according to this patentapplication for the production of pharmaceutical agents withantiinflammatory action fall within the scope of the general formulathat is contained in WO 98/54159, but are not preferred as a group ordirectly disclosed as compounds there. They are thus novel and also meetthe patenting requirement of inventive activity because of theantiinflammatory action that was found and that is dissociated fromundesirable metabolic effects or other effects.

[0055] Undesirable actions/effects in the context of this invention aremetabolic actions or else bonds to other steroid receptors.

[0056] The compounds of general formula I cited by name below fallnamely within the scope of the general formula that is cited in WO98/54159 but are not previously described by name there. They are thusnovel and also meet the patenting requirement of inventive activitybecause of the antiinflammatory action that was found and that isdissociated from undesirable side effects.

[0057] These compounds as such therefore also belong to the subjectmatter of this invention and are listed below.

[0058] Their naming is to be illustrated in the following example:

6-[4-(2-Chloro-3-R⁵-4-R⁶-5-R⁷-6-R⁸-phenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0059] The following compounds are the subject of this invention:

[0060]5-[4-(5-Fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-phthalide

[0061]6-[4-(2-chloro-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0062]5-[4-(5-fluoro-2-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-phthalide

[0063]6-[4-(5-fluoro-2-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0064]5-[4-(3-fluoro-4-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-phthalide

[0065]6-[4-(3-fluoro-4-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0066]6-[4-(2-bromo-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0067]6-[4-(indan-4′-yl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0068] (−)6-[4-(indan-4′-yl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0069] (+)6-[4-(indan-4′-yl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0070]6-[4-(5-fluoro-2-vinylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0071] (−)6-[4-(5-fluoro-2-vinylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0072] (+)6-[4-(5-fluoro-2-vinylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0073]6-[2-hydroxy-4-methyl-2-trifluoromethyl-4-(4-trifluoromethyphenyl)-valeroylamino]-4-methyl-2,3-benzoxazin-1-one

[0074] (−)6-[2-hydroxy-4-methyl-2-trifluoromethyl-4-(4-trifluoromethylphenyl)-valeroylamino]-4-methyl-2,3-benzoxazin-1-one

[0075] (+)6-[2-hydroxy-4-methyl-2-trifluoromethyl-4-(4-trifluoromethylphenyl)-valeroylamino]-4-methyl-2,3-benzoxazin-1-one

[0076]6-[4-(2-bromo-3,5-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0077] (−)6-[4-(2-bromo-3,5-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0078] (+)6-[4-(2-bromo-3,5-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0079]6-[4-(3,5-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0080] (−)6-[4-(3,5-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0081] (+)6-[4-(3,5-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0082]6-[4-(2-cyano-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0083]6-[4-(2-ethenyl-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0084]6-[4-(2-ethyl-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0085]6-[4-(5-fluoro-2-phenylphenyl-2-hydroxy-4-methy-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0086]6-[4-{5-fluoro-2-(furan-2′-yl)phenyl}-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0087]6-[4-(2-bromo-3,5-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0088]6-[2-hydroxy-4-methyl-2-trifluoromethyl-4-(1-naphthyl)-valeroylamino]-4-methyl-2,3-benzoxazin-1-one

[0089] (−)6-[2-hydroxy-4-methyl-2-trifluoromethyl-4-(1-naphthyl)-valeroylamino]-4-methyl-2,3-benzoxazin-1-one

[0090] (+)6-[2-hydroxy-4-methyl-2-trifluoromethyl-4-(1-naphthyl)-valeroylamino]-4-methyl-2,3-benzoxazin-1-one

[0091]6-[4-(2-chlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0092](−)-6-[4-(2-chlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0093](+)-6-[4-(2-chlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0094]6-[4-(2-chloro-3-fluoro-phenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0095] (−)6-[4-(2-chloro-3-fluoro-phenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0096](+)-6-[4-(2-chloro-3-fluoro-phenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0097]6-[4-(2-chloro-4-fluoro-phenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0098](−)-6-[4-(2-chloro-4-fluoro-phenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0099](+)-6-[4-(2-chloro-4-fluoro-phenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0100]6-[4-(2-chloro-6-fluoro-phenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0101](−)-6-[4-(2-chloro-6-fluoro-phenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0102](+)-6-[4-(2-chloro-6-fluoro-phenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0103]6-[4-(2,3-dichlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0104](−)-6-[4-(2,3-dichlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0105](+)-6-[4-(2,3-dichlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0106]6-[4-(2,4-dichlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0107](−)-6-[4-(2,4-dichlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0108](+)-6-[4-(2,4-dichlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0109]6-[4-(2,5-dichlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0110](−)-6-[4-(2,5-dichlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroy]-amino-4-methyl-2,3-benzoxazin-1-one

[0111](+)-6-[4-(2,5-dichlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0112]6-[4-(4-bromo-2-chlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroy]-amino-4-methyl-2,3-benzoxazin-1-one

[0113](−)-6-[4-(4-bromo-2-chlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0114](+)-6-[4-(4-bromo-2-chlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0115]6-[4-(2-chloro-3-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0116](−)-6-[4-(2-chloro-3-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0117](+)-6-[4-(2-chloro-3-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0118]6-[4-(2-chloro-3-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0119](−)-6-[4-(2-chloro-3-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0120](+)-6-[4-(2-chloro-3-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0121]6-[4-(2-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0122](−)-6-[4-(2-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0123](+)-6-[4-(2-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0124]6-[4-(2,3-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0125](−)-6-[4-(2,3-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0126](+)-6-[4-(2,3-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0127](−)-6-[4-(2,3-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylhexanoylamino]-4-methyl-2,3-benzoxazin-1-one

[0128](+)-6-[4-(2,3-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylhexanoylamino]-4-methyl-2,3-benzoxazin-1-one

[0129]6-[4-(2,4-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0130](−)-6-[4-(2,4-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0131](+)-6-[4-(2,4-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0132]6-[4-(2,5-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0133](−)-6-[4-(2,5-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0134](+)-6-[4-(2,5-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0135]6-[4-(2,6-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0136](−)-6-[4-(2,6-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0137](+)-6-[4-(2,6-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0138]6-[4-(2,3,5-trifluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0139](−)-6-[4-(2,3,5-trifluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0140](+)-6-[4-(2,3,5-trifluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0141]6-[4-(2,3,4-trifluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0142](−)-6-[4-(2,3,4-trifluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0143](+)-6-[4-(2,3,4-trifluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0144]6-[4-(3-chloro-2-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0145](−)-6-[4-(3-chloro-2-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl-amino]-4-methyl-2,3-benzoxazin-1-one

[0146](+)-6-[4-(3-chloro-2-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0147]6-[4-(4-chloro-2-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0148](−)-6-[4-(4-chloro-2-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl-amino]-4-methyl-2,3-benzoxazin-1-one

[0149](+)-6-[4-(4-chloro-2-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl-amino]-4-methyl-2,3-benzoxazin-1-one

[0150]6-[4-(2-fluoro-3-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0151] (−)6-[4-(2-fluoro-3-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl-amino]-4-methyl-2,3-benzoxazin-1-one

[0152] (+)6-[4-(2-fluoro-3-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0153]6-[4-(2-bromophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0154](−)-6-[4-(2-bromophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0155](+)-6-[4-(2-bromophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0156]6-[4-(2-trifluoromethyl-phenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0157](−)-6-[4-(2-trifluoromethyl-phenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0158](+)-6-[4-(2-trifluoromethyl-phenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0159]6-[4-(4-fluoro-2-trifluoromethyl-phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0160](−)-6-[4-(4-fluoro-2-trifluoromethyl-phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0161](+)-6-[4-(4-fluoro-2-trifluoromethyl-phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0162]6-[4-(5-fluoro-2-trifluoromethyl-phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0163](−)-6-[4-(5-fluoro-2-trifluoromethyl-phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0164](+)-6-[4-(5-fluoro-2-trifluoromethyl-phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0165]6-[4-(5-chloro-2-trifluoromethyl-phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0166](−)-6-[4-(5-chloro-2-trifluoromethyl-phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0167](+)-6-[4-(5-chloro-2-trifluoromethyl-phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0168]6-[3-{1-(2-chlorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0169] (−)6-[3-{1-(2-chlorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0170] (+)6-[3-{1-(2-chlorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0171]6-[3-{1-(2-chlorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0172](−)-6-[3-{1-(2-chlorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0173](+)-6-[3-{1-(2-chlorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methy-2,3-benzoxazin-1-one

[0174]6-[3-{1-(2-chlorophenyl)-cyclopentyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0175](−)-6-[3-{1-(2-chlorophenyl)-cyclopentyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0176](+)-6-[3-{1-(2-chlorophenyl)-cyclopentyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0177]6-[3-{1-(2-chloro-4-fluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0178](−)-6-[3-{1-(2-chloro-4-fluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethyl-propionyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0179](+)-6-[3-{1-(2-chloro-4-fluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethyl-propionyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0180]6-[3-{1-(2-chloro-4-fluorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0181](−)-6-[3-{1-(2-chloro-4-fluorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethyl-propionyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0182](+)-6-[3-{1-(2-chloro-4-fluorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethyl-propionyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0183]6-[3-{1-(2-chloro-5-fluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0184](−)-6-[3-{1-(2-chloro-5-fluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0185](+)-6-[3-{1-(2-chloro-5-fluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethyl-propionyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0186]6-[3-{1-(2-chloro-5-fluorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0187](−)-6-[3-{1-(2-chloro-5-fluorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethyl-propionyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0188](+)-6-[3-{1-(2-chloro-5-fluorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethyl-propionyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0189]6-[3-{1-(2,4-dichlorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0190](−)-6-[3-{1-(2,4-dichlorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0191](+)-6-[3-{1-(2,4-dichlorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0192]6-[3-{1-(2,4-dichlorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0193](−)-6-[3-{1-(2,4-dichlorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0194](+)-6-[3-{1-(2,4-dichlorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0195]6-[3-{1-(2-trifluoromethyl-phenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0196](−)-6-[3-{1-(2-trifluoromethyl-phenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0197](+)-6-[3-{1-(2-trifluoromethyl-phenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0198]6-[3-{1-(2-trifluoromethyl-phenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0199](−)-6-[3-{1-(2-trifluoromethyl-phenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0200](+)-6-[3-{1-(2-trifluoromethyl-phenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0201]6-[3-{1-(2-trifluoromethyl-phenyl)-cyclohexyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0202] (−)6-[3-{1-(2-trifluoromethyl-phenyl)-cyclohexyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0203] (+)6-[3-{1-(2-trifluoromethyl-phenyl)-cyclohexyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0204]6-[3-{1-(5-fluoro-2-trifluoromethyl-phenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0205](−)-6-[3-{1-(5-fluoro-2-trifluoromethyl-phenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0206](+)-6-[3-{1-(5-fluoro-2-trifluoromethyl-phenyl)-cyclopropyl}-2-hydroxy-2-trifluromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0207]6-[3-{1-(5-fluoro-2-trifluoromethyl-phenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0208](−)-6-[3-{1-(5-fluoro-2-trifluoromethyl-phenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0209](+)-6-[3-{1-(5-fluoro-2-trifluoromethyl-phenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0210]6-[3-{1-(2-fluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one

[0211](−)-6-[3-{1-(2-fluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one

[0212](+)-6-[3-{1-(2-fluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one

[0213]6-[3-{1-(2-fluorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one

[0214](−)-6-[3-{1-(2-fluorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one

[0215](+)-6-[3-{1-(2-fluorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one

[0216]6-[3-{1-(2-fluorophenyl)-cyclopentyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one

[0217](−)-6-[3-{1-(2-fluorophenyl)-cyclopentyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one

[0218](+)-6-[3-{1-(2-fluorophenyl)-cyclopentyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one

[0219]6-[3-{1-(2-fluorophenyl)-cyclohexyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one

[0220](−)-6-[3-{1-(2-fluorophenyl)-cyclohexyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one

[0221](+)-6-[3-{1-(2-fluorophenyl)-cyclohexyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one

[0222]6-[3-{1-(2,3-difluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one

[0223](−)-6-[3-{1-(2,3-difluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one

[0224](+)-6-[3-{1-(2,3-difluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl-amino]-4-methyl-2,3-benzoxazin-1-one

[0225]6-[3-{1-(2,3-difluorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one

[0226] (−)6-[3-{1-(2,3-difluorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one

[0227] (+)6-[3-{1-(2,3-difluorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one

[0228]6-[3-{1-(2,5-difluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one

[0229](−)-6-[3-{1-(2,5-difluorophenyl)-cyanopropyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one

[0230](+)-6-[3-{1-(2,5-difluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one

[0231]6-[3-{1-(2,3,5-trifluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one

[0232](−)-6-[3-{1-(2,3,5-trifluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one

[0233](+)-6-[3-{1-(2,3,5-trifluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl-amino]-4-methyl-2,3-benzoxazin-1-one

[0234]6-[3-{1-(2,3,5-trifluorophenyl)-cyclobuty}1-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one

[0235](−)-6-[3-{1-(2,3,5-trifluorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one

[0236](+)-6-[3-{1-(2,3,5-trifluorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl-amino]-4-methyl-2,3-benzoxazin-1-one

[0237]6-[3-{1-(2-bromophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one

[0238](−)-6-[3-{1-(2-bromophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one

[0239](+)-6-[3-{1-(2-bromophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one

[0240]6-[2-hydroxy-4-methyl-4-(3-methyl-2-nitrophenyl)-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0241] (−)6-[2-hydroxy-4-methyl-4-(3-methyl-2-nitrophenyl)-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0242] (+)6-[2-hydroxy-4-methyl-4-(3-methyl-2-nitrophenyl)-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0243]5-[4-(2-amino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl-amino]-phthalide

[0244] (−)5-[4-(2-amino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl-amino]-phthalide

[0245] (+)5-[4-(2-amino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl-amino]-phthalide

[0246]6-[4-(2-amino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl-amino]-4-methyl-2,3-benzoxazin-1-one

[0247](−)-6-[4-(2-amino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl-amino]-4-methyl-2,3-benzoxazin-1-one

[0248] (+)6-[4-(2-amino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0249]6-[4-(2-acetylamino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one

[0250] (−)6-[4-(2-acetylamino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one

[0251] (+)6-[4-(2-acetylamino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one

[0252]5-[4-(2-acetylamino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide

[0253] (−)5-[4-(2-acetylamino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide

[0254] (+)5-[4-(2-acetylamino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide

[0255]5-[4-(5-fluoro-2-mesylaminophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide

[0256] (−)5-[4-(5-fluoro-2-mesylaminophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide

[0257] (+)5-[4-(5-fluoro-2-mesylaminophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide

[0258]6-[4-(2-bromo-3-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one

[0259] (−)6-[4-(2-bromo-3-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one

[0260] (+)6-[4-(2-bromo-3-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one

[0261]6-[4-(2-bromo-3-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one

[0262] (−)6-[4-(2-bromo-3-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one

[0263] (+)6-[4-(2-bromo-3-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one

[0264]6-[4-(2-bromo-3-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one

[0265](−)-6-[4-(2-bromo-3-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one

[0266](+)-6-[4-(2-bromo-3-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one

[0267]6-[4-(2,3-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylcaproylamino]-4-methyl-2,3-benzoxazin-1-one

[0268] (−)6-[4-(2,3-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylcaproylamino]-4-methyl-2,3-benzoxazin-1-one

[0269] (+)6-[4-(2,3-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylcaproylamino]-4-methyl-2,3-benzoxazin-1-one

[0270]6-[4-(2,6-difluorophenyl)-2-hydroxy-4-methyl-4-trifluoromethylcaproylamino]-4-methyl-2,3-benzoxazin-1-one

[0271] (−)6-[4-(2,6-difluorophenyl)-2-hydroxy-4-methyl-4-trifluoromethylcaproylamino]-4-methyl-2,3-benzoxazin-1-one

[0272] (+)6-[4-(2,6-difluorophenyl)-2-hydroxy-4-methyl-4-trifluoromethylcaproylamino]-4-methyl-2,3-benzoxazin-1-one

[0273]6-{3-[4-(2-chloro-5-fluorophenyl)-tetrahydropyran-4-yl]-2-hydroxy-2-trifluoromethylpropionylamino}-4-methyl-2,3-benzoxazin-1-one

[0274] (−)6-{3-[4-(2-chloro-5-fluorophenyl)-tetrahydropyran-4-yl]-2-hydroxy-2-trifluoromethylpropionylamino}-4-methyl-2,3-benzoxazin-1-one

[0275] (+)6-{3-[4-(2-chloro-5-fluorophenyl)-tetrahydropyran-4-yl]-2-hydroxy-2-trifluoromethylpropionylamino}-4-methyl-2,3-benzoxazin-1-one

[0276] A special aspect of this invention are the above-indicated2,3-benzoxazin-1-ones.

[0277] Another aspect of this invention are the above-indicatedcompounds, whose 2,3-benzoxazin-1-one in 3-position carries a methylgroup.

[0278] If the compounds of general formula I are present as salts, thiscan be, for example, in the form of hydrochloride, sulfate, nitrate,phosphate, pivalate, maleate, fumarate, tartrate, benzoate, mesylate,citrate or succinate.

[0279] If the compounds according to the invention are present asracemic mixtures, they can be separated into the pure, optically activeforms according to the methods of racemate separation that are familiarto one skilled in the art. For example, the racemic mixtures can beseparated into the pure isomers by chromatography on an even opticallyactive carrier material (CHIRALPAK AD®). It is also possible to esterifythe free hydroxy group in a racemic compound of general formula I withan optically active acid and to separate the diastereoisomer esters thatare obtained by fractionated crystallization or by chromatography and tosaponify the separated esters in each case to form the optically pureisomers. As an optically active acid, for example, mandelic acid,camphorsulfonic acid or tartaric acid can be used. Process for theProduction of the Compounds According to the Invention

[0280] The compounds according to the invention can be obtained by thechain C(R¹) (R²)—CH₂—C (OH)(R³) —B—NH—Ar being built up starting from acommercially available phenyl compound or a phenyl compound that isavailable according to known methods, whereby radical R³ is introducedin the last step or the ring system of formulas (1) or (2) (═Ar) isintroduced with the formation of the amide bond B—NH—Ar.

[0281] Compounds that were produced according to one of the processesbelow and in which A is a substituted aromatic ring, optionally can besubstituted selectively at this aromatic radical according to knownprocesses. Examples of this process are the catalytic hydrogenation ofmultiple bonds, the nitration and the halogenation. Halogen and nitrosubstitutions offer, moreover, possible further modifications. Thus, forexample, aryl bromides can be reacted with boron, tin or zinc reagentsunder palladium catalysis in the way that is known to one skilled in theart. Nitro compounds can be reduced to aniline derivatives, for examplehydrogenolytically, or with metals, such as, e.g., iron or zinc. Theaniline derivatives can be further reacted after diazotization in aknown way, for example in terms of Sandmeyer reactions.

[0282] (A)

[0283] An α-ketocarboxylic acid of general formula II

[0284]  in which A, R¹ and R² have the meanings that are indicated informula I,

[0285] is either optionally esterified with a compound of generalformula

(R¹²)₃SiR³  (III)

[0286] in which R³ has the meaning that is indicated in general formulaI, and R¹² means a C₁-C₅ alkyl group,

[0287] in the presence of a catalyst, or is reacted with an alkyl metalcompound, for example a Grignard reagent or a lithium alkyl, to form acompound of formula IV

[0288] As catalyst, fluoride salts or basic compounds, such as alkalicarbonates, are suitable (J. Am. Chem. Soc. 111, 393 (1989)).

[0289] The ester is optionally cleaved again and then reacted with acompound of general formula V

Ar—NH—R¹³  , (V)

[0290] whereby R¹³ means a hydrogen atom or a C₁-C₅ acyl group, and Arhas the meaning that is indicated in general formula I,

[0291] whereby then radical R¹³ is cleaved off to obtain a compound offormula I or is reacted directly with a compound of general formula

Ar—NH—R¹³  (V)

[0292] whereby R¹³ means a hydrogen atom or a C₁-C₅ acyl group, and Arhas the meaning that is indicated in general formula I, optionally afteractivation of the acid function by, e.g., conversion into the acidchloride, whereby then radical R¹³ is cleaved off in any sequence and isreacted with a compound of general formula III

(R¹²)₃—SiR³  (III)

[0293] in which R³ and R¹² have the above-indicated meanings, to obtaina compound of formula I.

[0294] (B)

[0295] A compound of general formula VI

[0296]  in which A, B, R¹, R², and R³ have the meaning that is indicatedin formula I and LG means any leaving group, is reacted with a compoundof general formula V

Ar—NH—R¹³  (V)

[0297] whereby R¹³ means a hydrogen atom or a C₁-C₅ acyl group, and Arhas the meaning that is indicated in general formula I, whereby thenradical R¹³ is cleaved off to obtain a compound of formula I.

[0298] In this case, the compound of general formula VI can optionallyalso be formed only as intermediate product, which can be isolated, ifdesired, or else can be produced only in situ, e.g., this can be an acidchloride that is formed intermediately from a corresponding carboxylicacid. As leaving groups, in this respect, for example, a fluorine,chlorine or bromine atom, or, if no intermediate acid chloride isformed, the mesylate radical or tosylate radical, can be mentioned.

[0299] The binding of substances to the glucocorticoid receptor (GR) isexamined with the aid of a recombinantly produced receptor. Cytosolpreparations of Sf9 cells, which had been infected with recombinantbaculoviruses, which code for the GR, are used for the binding studies.In comparison to the reference substance [³H]-dexamethasone, thesubstances show a high to very high affinity to the GR.

[0300] In addition, these compounds in the mineral corticoid receptor(MR)-binding test with use of cytosol preparations that consist of Sf9cells, which had been infected with baculoviruses that code for the MR,and with use of [³H]-aldosterone as a reference substance, showaffinities to the MR.

[0301] As an essential molecular mechanism for the antiinflammatoryaction of glucocorticoids, the GR-mediated inhibition of thetranscription of cytokines, adhesion molecules, enzymes and otherpro-inflammatory factors can be seen. This inhibition is produced by aninteraction of the GR with other transcription factors, e.g., AP-1 andNF-kappa-B (for a survey, see Cato, A. C. B. and Wade, E., BioEssays 18,371-378, 1996).

[0302] The compounds of general formula I according to the inventioninhibit the secretion of the cytokine IL-8 that is triggered bylipopolysaccharide (LPS) in human monocyte cell line THP-1. Theconcentration of the cytokines was determined in the supernatant withuse of commercially available ELISA kits.

[0303] The antiinflammatory actions of the compounds of general formulaI were tested in the animal experiment by testing in the crotonoil-induced inflammation in rats and mice (J. Exp. Med. (1995), 182,99-108). In this connection, croton oil in ethanolic solution wasadministered topically to the animals' ears. The test substances werealso administered topically or systemically simultaneously with or twohours before the croton oil. After 16-24 hours, the ear weight wasmeasured as a yardstick of the inflammatory edema, the peroxidaseactivity was measured as a yardstick of the invasions of granuloctyes,and the elastase activity was measured as a yardstick of the invasionsof neutrophilic granuloctyes. In this test, the compounds of generalformula I inhibit the three above-mentioned inflammation parameters bothafter topical administration and after systemic administration.

[0304] One of the most frequent undesirable effects of a glucocorticoidtherapy is the so-called “steroid diabetes” [cf. Hatz, H. J.,Glucocorticoide: Immunologische Grundlagen, Pharmakologie undTherapierichtlinien [Glucocorticoids: Immunological Bases, Pharmacologyand Therapy Guidelines], Wissenschaftliche Verlagsgesellschaft mbH,Stuttgart, 1998]. The reason for this is the stimulation of thegluconeogenesis in the liver by induction of the enzymes that areresponsible for this effect and by free amino acids, which develop fromthe degradation of proteins (catabolic action of glucocorticoids). A keyenzyme of the catabolic metabolism in the liver is the tyrosinaminotransferase (TAT). The activity of this enzyme can be determinedphotometrically from liver homogenates and represents a good yardstickof the undesirable metabolic actions of the glucocorticoids. To measurethe TAT induction, the animals are sacrificed 8 hours after the testsubstances are administered, the livers are removed, and the TATactivity in the homogenate is measured. In this test, at doses at whichthey have an antiinflammatory action, the compounds of general formula Iinduce little or no tyrosinamino transferase.

[0305] In summary, the new compounds of general formula I compared tothe previously used steroidal glucocorticoids have the followingadvantages:

[0306] nonsteroidal structure (i.e., the substances are also effectivein patients who, because of an allergic reaction to the steroid basicstructures of conventional glucocorticoids, can no longer access thelatter for therapy (cf. Lutz, ME, el-Azhary RA, Mayo Clin. Proc. 72,1141-1144, 1997).

[0307] good antiinflammatory action with little metabolic action

[0308] Because of their antiinflammatory and additional antiallergic,immunosuppressive and antiproliferative actions, the compounds ofgeneral formula I according to the invention can be used as medicationsfor treatment or prophylaxis of the following pathologic conditions inmammals and humans: In this case, the term “DISEASE” stands for thefollowing indications:

[0309] (i) Lung diseases, which coincide with inflammatory, allergicand/or proliferative processes:

[0310] Chronically obstructive lung diseases of any origin, mainlybronchial asthma

[0311] bronchitis of different origins

[0312] all forms of restrictive lung diseases, mainly allergicalveolitis,

[0313] all forms of pulmonary edema, mainly toxic pulmonary edema

[0314] sarcoidoses and granulomatoses, especially Boeck's disease

[0315] (ii) Rheumatic diseases/auto-immune diseases/degenerative jointdiseases, which coincide with inflammatory, allergic and/orproliferative processes:

[0316] All forms of rheumatic diseases, especially rheumatoid arthritis,acute rheumatic fever, polymyalgia rheumatica,

[0317] reactive arthritis

[0318] inflammatory soft-tissue diseases of other origins

[0319] arthritic symptoms in degenerative joint diseases (arthroses)

[0320] traumatic arthritides

[0321] collagen diseases of other origins, e.g., systemic lupuserythematodes, scleroderma, polymyositis, dermatomyositis, Sjögren'ssyndrome, Still syndrome, Felty's syndrome

[0322] (iii) Allergies, which coincide with inflammatory and/orproliferative processes:

[0323] All forms of allergic reactions, e.g., Quincke's edema, hayfever, insect bites, allergic reactions to pharmaceutical agents, bloodderivatives, contrast media, etc., anaphylactic shock, urticaria,contact dermatitis

[0324] (iv) Vascular diseases (vasculitis)

[0325] Panarteritis nodosa, temporal arteritis, erythema nodosum

[0326] (v) Dermatological diseases, which coincide with inflammatory,allergic and/or proliferative processes:

[0327] Atopic dermatitis (mainly in children)

[0328] psoriasis

[0329] pityriasis rubra pilaris

[0330] erythematous diseases, triggered by different noxae, e.g.,radiation, chemicals, burns, etc.

[0331] bullous dermatoses

[0332] diseases of the lichenoid group

[0333] itching (e.g., of allergic origins)

[0334] seborrheal eczema

[0335] rosacea

[0336] pemphigus vulgaris

[0337] erythema exudativum multiforme

[0338] balanitis

[0339] vulvitis

[0340] hair loss, such as alopecia areata

[0341] cutaneous T-cell lymphoma

[0342] (vi) Nephropathies, which coincide with inflammatory, allergicand/or proliferative processes:

[0343] Nephrotic syndrome

[0344] all nephritides

[0345] (vii) Liver diseases, which coincide with inflammatory, allergicand/or proliferative processes:

[0346] Acute liver cell decomposition

[0347] acute hepatitis of different origins, e.g., virally-, toxically-or pharmaceutical agent-induced

[0348] chronically aggressive and/or chronically intermittent hepatitis

[0349] (viii) Gastrointestinal diseases, which coincide withinflammatory, allergic and/or proliferative processes:

[0350] Regional enteritis (Crohn's disease)

[0351] ulcerative colitis

[0352] gastritis

[0353] reflux esophagitis

[0354] gastroenteritides of other origins, e.g., native sprue

[0355] (ix) Proctological diseases, which coincide with inflammatory,allergic and/or proliferative processes:

[0356] Anal eczema

[0357] fissures

[0358] hemorrhoids

[0359] idiopathic proctitis

[0360] (x) Eye diseases, which coincide with inflammatory, allergicand/or proliferative processes:

[0361] Allergic keratitis, uveitis, iritis

[0362] conjunctivitis

[0363] blepharitis

[0364] optic neuritis

[0365] chorioiditis

[0366] sympathetic ophthalmia

[0367] (xi) Diseases of the ear-nose-throat area, which coincide withinflammatory, allergic and/or proliferative processes:

[0368] Allergic rhinitis, hay fever

[0369] otitis externa e.g., caused by contact dermatitis, infection,etc.

[0370] otitis media

[0371] (xii) Neurological diseases, which coincide with inflammatory,allergic and/or proliferative processes:

[0372] Cerebral edema, mainly tumor-induced cerebral edema

[0373] multiple sclerosis

[0374] acute encephalomyelitis

[0375] meningitis

[0376] different forms of convulsions, e.g., infantile nodding spasms

[0377] (xiii) Blood diseases, which coincide with inflammatory, allergicand/or proliferative processes:

[0378] Acquired hemolytic anemia

[0379] idiopathic thrombocytopenia

[0380] (xiv) Tumor diseases, which coincide with inflammatory, allergicand/or proliferative processes:

[0381] Acute lymphatic leukemia

[0382] malignant lymphoma

[0383] lymphogranulomatoses

[0384] lymphosarcoma

[0385] extensive metastases, mainly in breast, bronchial and prostatecancers

[0386] (xv) Endocrine diseases, which coincide with inflammatory,allergic and/or proliferative processes:

[0387] Endocrine orbitopathy

[0388] thyrotoxic crisis

[0389] de Quervain's thyroiditis

[0390] Hashimoto's thyroiditis

[0391] hyperthyroidism

[0392] (xvi) Organ and tissue transplants, graft-versus-host disease

[0393] (xvii) Severe shock conditions, e.g., anaphylactic shock,systemic inflammatory response syndrome (SIRS)

[0394] (xviii) Substitution therapy, with:

[0395] Innate primary suprarenal insufficiency, e.g., congenitaladrenogenital syndrome

[0396] acquired primary suprarenal insufficiency, e.g., Addison'sdisease, autoimmune adrenalitis, meta-infective, tumors, metastases,etc.

[0397] innate secondary suprarenal insufficiency, e.g., congenitalhypopituitarism

[0398] acquired secondary suprarenal insufficiency, e.g.,meta-infective, tumors, etc.

[0399] (xix) vomiting, which coincides with inflammatory, allergicand/or proliferative processes:

[0400] e.g., in combination with a 5-HT₃-antagonist incytostatic-agent-induced vomiting

[0401] (xx) Pain with inflammatory origins, e.g., lumbago.

[0402] The compounds of general formula I according to the invention canalso be used for therapy and prophylaxis of additional pathologicconditions that are not mentioned above, for which syntheticglucocorticoids are now used (see in this connection Hatz, H. J.,Glucocorticoide: Immunologische Grundlagen, Pharmakologie undTherapierichtlinien, Wissenschaftliche Verlagsgesellschaft mbH,Stuttgart, 1998).

[0403] All previously mentioned indications (i) to (xx) are described indetail in Hatz, H. J., Glucocorticoide: Immunologische Grundlagen,Pharmakologie und Therapierichtlinien, WissenschaftlicheVerlagesgesellschaft mbH, Stuttgart, 1998.

[0404] For the therapeutic actions in the above-mentioned pathologicconditions, the suitable dose is different and it depends on, forexample, the active strength of the compound of general formula I, thehost, the type of administration and the type and severity of theconditions that are to be treated, as well as the use as prophylacticagent or therapeutic agent.

[0405] In addition, the invention provides

[0406] (i) The use of a compound of the invention according to formula Ior its mixture for the production of a medication for treating aDISEASE;

[0407] (ii) a process for treating a DISEASE, and said process comprisesan administration of an amount of compound according to the invention,whereby the amount suppresses the disease and whereby the amount ofcompound is given to a patient who requires such a medication;

[0408] (iii) a pharmaceutical composition for treating a DISEASE, andsaid treatment comprises one of the compounds according to the inventionor its mixture and at least one pharmaceutical adjuvant and/or vehicle.

[0409] In general, satisfactory results are to be expected in animalswhen the daily doses comprise a range of 1 μg to 100,000 μg of thecompound according to the invention per kg of body weight. In largermammals, for example humans, a recommended daily dose lies in the rangeof 1 μg to 100,000 μg per kg of body weight. Preferred is a dose of 10to 30,000 μg per kg of body weight, more preferably a dose of 10 to10,000 μg per kg of body weight. For example, this dose is suitablyadministered several times daily. For treating acute shock (e.g.,anaphylactic shock), individual doses can be given that lie considerablyabove the above-mentioned doses.

[0410] The formulation of the pharmaceutical preparations based on thenew compounds is carried out in a way that is known in the art, by theactive ingredient being processed with the vehicles, fillers, substancesthat influence decomposition, binding agents, humectants, lubricants,absorbents, diluents, flavoring correctives, staining agents, etc. thatare commonly used in galenicals and converted into the desired form ofadministration. In this case, reference is to be made to Remington'sPharmaceutical Science, 15th Ed. Mack Publishing Company, EastPennsylvania (1980).

[0411] For oral administration, especially tablets, coated tablets,capsules, pills, powders, granulates, lozenges, suspensions, emulsionsor solutions are suitable.

[0412] For parenteral administration, injection and infusionpreparations are possible.

[0413] For intra-articular injection, correspondingly prepared crystalsuspensions can be used.

[0414] For intramuscular injection, aqueous and oily injection solutionsor suspensions and corresponding depot preparations can be used.

[0415] For rectal administration, the new compounds can be used in theform of suppositories, capsules, solutions (e.g., in the form of enemas)and ointments, both for systemic and for local therapy.

[0416] For pulmonary administration of the new compounds, the latter canbe used in the form of aerosols and inhalants.

[0417] For local application to eyes, outer ear channels, middle ears,nasal cavities, and paranasal sinuses, the new compounds can be used asdrops, ointments and tinctures in corresponding pharmaceuticalpreparations.

[0418] For topical application, formulations in gels, ointments, fattyointments, creams, pastes, powders, milk and tinctures are possible. Thedosage of the compounds of general formula I should be 0.01%-20% inthese preparations to achieve an adequate pharmacological action.

[0419] The invention also comprises the compounds of general formula Iaccording to the invention as therapeutic active ingredients. Inaddition, the compounds of general formula I according to the inventionare part of the invention as therapeutic active ingredients togetherwith pharmaceutically compatible and acceptable adjuvants and vehicles.The invention also comprises a pharmaceutical composition that containsone of the pharmaceutically active compounds according to the inventionor mixture thereof and a pharmaceutically compatible salt orpharmaceutically compatible adjuvant and vehicle.

[0420] The examples below are used for a more detailed explanation ofthe invention without intending that it be limited to these examples.The syntheses of important precursors, which are not disclosed withinthe scope of the experimental part, are already prior art and can bededuced in the example from WO 98/54159.

[0421] Experimental Part

EXAMPLE 16-[4-(5-Fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-oneEXAMPLE 25-[4-(5-Fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]phthalide

[0422] Precursors

2-(5-Fluoro-2-methylphenyl)-2-methylpropionitrile

[0423] 5.25 g of (5-fluoro-2-methylphenyl)acetonitrile and 5.25 ml ofmethyl iodide are dissolved in 70 ml of dimethylformamide and mixed with2.7 g of sodium hydride (80%) for 2.5 hours while being cooled with ice.After 3 hours at 0° C. and 16 hours at room temperature, it is mixedwith ice water and ethyl acetate, acidified with 1 M hydrochloric acid,and the ethyl acetate phase is washed with water, dried (Na₂SO₄) andconcentrated by evaporation. 6.1 g of2-(5-fluoro-2-methylphenyl)-2-methylpropionitrile is obtained as an oil.

2-(5-Fluoro-2-methylphenyl)-2-methylpropionaldehyde

[0424] 6.1 g of 2-(5-fluoro-2-methylphenyl)-2-methylpropionitrile,dissolved in 60 ml of toluene, is mixed at −70° C. for 45 minutes with44 ml of 1.2 M diisobutylaluminum hydride solution in toluene. After 4hours at −78° C., 120 ml of ethyl acetate is added in drops. It isheated to room temperature and washed three times with 2N sulfuric acidand once with water. The ethyl acetate phase is dried (Na₂SO₄) andconcentrated by evaporation. After distillation, 5.3 g of2-(5-fluoro-2-methylphenyl)-2-methylpropionaldehyde of boiling point120° C./0.031 hPa is obtained.

4-(5-Fluoro-2-methylphenyl)-4-methyl-2-oxovaleric acid

[0425] A solution of 8.04 ml of 2-diethylphosphono-2-ethoxyaceticacid-ethyl ester in 40 ml of tetrahydrofuran is mixed with 16.5 ml of a2 M solution of lithium diisopropylamide intetrahydrofuran-heptane-toluene within 20 minutes while being cooledwith ice, and it is stirred for 30 minutes at 0° C. Within 30 minutes, asolution of 5.2 g of 2-(5-fluoro-2-methylphenyl)-2-methylpropionaldehydein 30 ml of tetrahydrofuran is added in drops to it at 0° C. After 20hours at room temperature, 2N sulfuric acid is added, it is extractedwith ethyl acetate, dried (Na₂SO₄) and concentrated by evaporation. Thecrude product is saponified with 100 ml of 2 M sodium hydroxidesolution. 5 g of acid is obtained, which is refluxed for several hourswith 450 ml of 2N sulfuric acid while being stirred vigorously. Afterextraction with ethyl acetate and washing with water, 4 g of4-(5-fluoro-2-methylphenyl)-4-methyl-2-oxovaleric acid is obtained as ayellowish oil.

5-[4-(5-Fluoro-2-methylphenyl)-4-methyl-2-oxovaleroylamino]-phthalide

[0426] 950 mg of 4-(5-fluoro-2-methylphenyl)-4-methyl-2-oxovaleric acidin 15 ml of dimethylacetamide is mixed at −10° C. with 0.322 ml ofthionyl chloride, stirred for 30 minutes at −10° C. and for 1 hour at 0°C. and purified with 750 mg of 5-aminophthalide. After 16 hours at roomtemperature, it is mixed with 2 M hydrochloric acid and ethyl acetate,the organic phase is washed neutral with water, dried (Na₂SO₄) andconcentrated by evaporation. After chromatography on silica gel withhexane-ethyl acetate (3:2) and recrystallization from diisopropyl ether,486 mg of5-[4-(5-fluoro-2-methylphenyl)-4-methyl-2-oxovaleroylamino]phthalide offlash point 153° C. is obtained.

6-[4-(5-Fluoro-2-methylphenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0427] was obtained analogously to5-[4-(5-fluoro-2-methylphenyl)-4-methyl-2-oxovaleroylamino]phthalidewith use of 4-(5-fluoro-2-methylphenyl)-4-methyl-2-oxovaleric acid and6-amino-2,3-benzoxazin-1-one, flash point 186° C.

6-[4-(5-Fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0428]

[0429] 514 mg of6-[4-(5-fluoro-2-methylphenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-onein 10 ml of dimethylformamide is purified at 0° C. with 192 mg of cesiumcarbonate and 0.44 ml of trifluoromethyl(trimethyl)silane. After 1 hourat 0° C. and 16 hours at room temperature, it is again cooled to 0° C.and mixed with 1.3 ml of a 1 M tetrabutylammonium fluoride solution intetrahydrofuran. After 30 minutes at 0° C., 2N sulfuric acid and ethylacetate are added, the ethyl acetate phase is washed with water, dried(Na₂SO₄) and concentrated by evaporation. After chromatography on silicagel with hexane-ethyl acetate (3:2), 220 mg of6-[4-(5-fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one,flash point 175-176° C., is obtained.

5-[4-(5-Fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]phthalide

[0430]

[0431] is obtained analogously to Example 1 from5-[4-(5-fluoro-2-methylphenyl)-4-methyl-2-oxovaleroylamino]phthalide,flash point 165-168° C.

[0432] Separation of the Enantiomers from Example 1

[0433] The enantiomer mixture of Example 1 is separated bychromatography on chiral support medium (CHIRALPAK AD®, DAICEL Company)with hexane/ethanol (9:1, vv). Thus obtained from 140 mg of racemateare:

[0434] (−)6-[4-(5-Fluoro-2-tolyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-oneas a first fraction: 57 mg, [flash point 203-204° C., α_(D)=−92.70°(c=0.5 in tetrahydrofuran)] and

[0435] (+)6-[4-(5-Fluoro-2-tolyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-oneas a second fraction: 56 mg, [flash point 202-203° C.].

EXAMPLE36-[4-(2-Chloro-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl-amino]-4-methyl-2,3-benzoxazin-1-one

[0436] Precursors

2-(2-Chloro-5-fluorophenyl)-2-methylpropionitrile

[0437] Analogously to the process that is described for2-(5-fluoro-2-methylphenyl)-2-methyl-propionitrile,2-(2-chloro-5-fluorophenyl)-2-methylpropionitrile is synthesized,boiling point 100° C./0.04 hPa.

2-(2-Chloro-5-fluorophenyl)-2-methylpropionaldehyde

[0438] Analogously to the process that is described for2-(5-fluoro-2-methylphenyl)-2-methylpropionaldehyde,2-(2-chloro-5-fluorophenyl)-2-methylpropionaldehyde, boiling point 120°C./0.04 hPa, is obtained.

4-(2-Chloro-5-fluorophenyl)-4-methyl-2-oxovaleric acid

[0439] Analogously to the process that is described for4-(5-fluoro-2-methylphenyl)-4-methyl-2-oxovaleric acid,4-(2-chloro-5-fluorophenyl)-4-methyl-2-oxovaleric acid is obtained as anoil.

[0440]6-[4-(2-Chloro-5-fluorophenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-oneis obtained from 4-(2-chloro-5-fluorophenyl)-4-methyl-2-oxovaleric acidand 6-amino-2,3-benzoxazin-1-one analogously to5-[4-(5-fluoro-2-methylphenyl)-4-methyl-2-oxovaleroylamino]phthalide,flash point 198-199° C.

6-[4-(2-Chloro-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0441]

[0442] was obtained analogously to Example 1 from6-[4-(2-chloro-5-fluorophenyl)-4-methyl-2-oxovaleroylamino]-2,3-benzoxazin-1-one,flash point 201-203° C.

[0443] Separation of the Enantiomers of Example 3

[0444] The enantiomer mixture of Example 3 is separated bychromatography on chiral support medium (CHIRALPAK AD®, DAICEL Company)with hexane/ethanol (19:1, vv). Thus obtained from 190 mg of racemateare:

[0445] (−)6-[4-(2-Chloro-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-oneas a first fraction: 61 mg, [flash point 247-249° C., α_(D)=−74.2°(c=0.5 in tetrahydrofuran)], and

[0446](+)-6-[4-(2-Chloro-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-oneas a second fraction: 74 mg, [flash point 247-249° C.].

[0447] Analogously to Example 3, the compounds of Tables 1-3 areobtained.

[0448] Chlorine compounds TABLE 1

Com- Flash point Isomerism or pound R5 R6 R7 R8 R1/R2 [° C.] [α]_(D) 1 HH H H CH₃ 169-171 racemate 2 H H H H CH₃ 198 −173.3 3 H H H H CH₃ 199(+)-form 4 F H H H CH₃ 189-192 racemate 5 F H H H CH₃ 189-192 −89.1 6 FH H H CH₃ 220-223 +78.2 7 H F H H CH₃ 208-209 racemate 8 H F H H CH₃ 179−77.1 9 H F H H CH₃ 181-182 +74.6 10 H H H F CH₃ 222-224 racemate 11 H HH F CH₃ 232-235 −110.0 12 H H H F CH₃ 230-233 +106.0 13 Cl H H H CH₃228-230 racemate 14 Cl H H H CH₃ 252-254 −32.8 15 Cl H H H CH₃ 255-256+29.3 16 H Cl H H CH₃ 249-253 racemate 17 H Cl H H CH₃ 253-255 −126.2 18H Cl H H CH₃ 252-256 (+)-form 19 H H Cl H CH₃ 210-211 −96.7 20 H H Cl HCH₃ 208-209 100.8 21 H Br H H CH₃ 155-157 racemate 22 H Br H H CH₃151-152 −16.6 23 H Br H H CH₃ 150-155 (+)-form 24 OH H H H CH₃ 235-241−75.3 25 OH H H H CH₃ 236-240 +76.0

[0449] Fluorine compounds TABLE 2

Com- Flash point Isomerism or pound R5 R6 R7 R8 R1/R2 [° C.] [α]_(D) 26H H H H CH₃ 220 −85.5 27 H H H H CH₃ 227 (+)-form 28 F H H H CH₃ 204racemate 29 F H H H CH₃ 204-205 −90.3 30 F H H H CH₃ 204-205 +83.0 31 HF H H CH₃ 175-176 −83.8 32 H F H H CH₃ 176-177 (+)-form 33 H H F H CH₃174 −81.5 34 H H F H CH₃ 174-176 (+)-form 35 H H H F CH₃ 205-210racemate 36 H H H F CH₃ 230-240 −71.3 37 H H H F CH₃ 240-245 (+)-form 38F H F H CH₃ 209 racemate 39 Cl H H H CH₃ 189-192 −64.0 40 Cl H H H CH₃184-187 (+)-form 41 H Cl H H CH₃ 239-141 racemate 42 H Cl H H CH₃210-215 −67.7 43 H Cl H H CH₃ 198-199 (+)-form 44 OCH₃ H H H CH₃ 197-200racemate

[0450] Bromine compounds TABLE 3

Com- Flash point Isomerism or pound R5 R6 R7 R8 R1/R2 [° C.] [α]_(D) 45H H H H CH₃ 186-191 racemate 46 H H H H CH₃ 209-211 −65.0 47 H H H H CH₃205-207 +66.0

EXAMPLE 45-[4-(5-Fluoro-2-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl-amino]phthalide

[0451] Precursors

2-(3-Fluorophenyl)-2-methylpropionitrile

[0452] Analogously to the process that is described for2-(5-fluoro-2-methylphenyl)-2-methylpropionitrile,2-(3-fluorophenyl)-2-methylpropionitrile is synthesized, boiling point102-103° C./0.029 hPa.

2-(3-Fluorophenyl)-2-methylpropionaldehyde

[0453] Analogously to the process that is described for2-(5-fluoro-2-methylphenyl)-2-methylpropionaldehyde,2-(3-fluorophenyl)-2-methylpropionaldehyde, boiling point 120° C./0 .04hPa, is obtained.

4-(3-Fluorophenyl)-4-methyl-2-oxovaleric acid

[0454] Analogously to the process that is described for4-(5-fluoro-2-methylphenyl)-4-methyl-2-oxovaleric acid,4-(3-fluorophenyl)-4-methyl-2-oxovaleric acid is obtained as an oil.

4-(3-Fluorophenyl)-4-methyl-2-oxovaleric acid-ethyl ester

[0455] 5.6 g of 4-(3-fluorophenyl)-4-methyl-2-oxovaleric acid and 0.197ml of sulfuric acid in 150 ml of ethanol are refluxed for 3 hours. Thesolvent is distilled off. The residue is taken up in ethyl acetate,washed with saturated sodium bicarbonate solution, dried (Na₂SO₄) andconcentrated by evaporation. After bulb tube distillation, 5.6 g of4-(3-fluorophenyl)-4-methyl-2-oxovaleric acid-ethyl ester with a boilingpoint of 130° C./0.04 hPA is obtained.

4-(3-Fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleric acidethyl ester

[0456] 5.3 g of 4-(3-fluorophenyl)-4-methyl-2-oxovaleric acid-ethylester in 60 ml of dimethylformamide is combined at 0° C. with 3.25 g ofcesium carbonate and 4.63 ml of trifluoromethyl(trimethyl)-silane. After1 hour at 0° C. and 16 hours at room temperature, it is cooled again to0° C. and mixed with 20 ml of a 1 M tetrabutylammonium fluoride solutionin tetrahydrofuran. After 30 minutes at 0° C., 2N sulfuric acid andethyl acetate are added to it, the ethyl acetate phase is washed withwater, dried (Na₂SO₄) and concentrated by evaporation. Afterchromatography on silica gel hexane-ethyl acetate (20:1) and bulb tubedistillation, 4.45 g of4-(3-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvalericacid-ethyl ester is obtained (boiling point 100° C./0.04 hpa).

4-(5-Fluoro-2-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvalericacid ethyl ester4-(3-Fluoro-4-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvalericacid ethyl ester

[0457] 3.3 g of4-(3-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleric acidethyl ester is dissolved in 20 ml of trifluoroacetic acid and mixed at0° C. with 0.84 ml of 100% nitric acid. After 3 hours at 0° C. and 16hours at room temperature, the batch is poured onto ice, thecrystallizate is suctioned off, washed with water and dried. Byrecrystallization from hexane, 2.5 g of4-(5-fluoro-2-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvalericacid-ethyl ester of flash point 66-670° C. is obtained.

[0458] From the mother liquor, after chromatography on silica gel withhexane-ethyl acetate (8:1), another 500 mg of4-(5-fluoro-2-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvalericacid-ethyl ester accumulates as a first fraction, and 800 mg of4-(3-fluoro-4-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvalericacid-ethyl ester as an oil accumulates as a second fraction.

4-(5-Fluoro-2-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvalericacid

[0459] 2.4 g of4-(5-fluoro-2-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvalericacid-ethyl ester is dissolved in 30 ml of ethanol and purified with 60ml of 1 M sodium hydroxide solution. After 2 days at room temperature,it is concentrated by evaporation, the residue is dissolved in water,acidified at 0° C. and extracted with ethyl acetate. The ethyl acetatephase is washed neutral with water, dried (Na₂SO₄) and concentrated byevaporation. After crystallization from diisopropyl ether,4-(5-fluoro-2-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvalericacid with a flash point of 130-131° C. is obtained.

5-[4-(5-Fluoro-2-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]phthalide

[0460]

[0461] 255 mg of4-(5-fluoro-2-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvalericacid in 3 ml of dimethyl acetamide is mixed at 0° C. with 0.105 ml ofthionyl chloride, stirred for 30 minutes at 0° C. and 45 minutes at roomtemperature and combined with 300 mg of 5-aminophthalide. After 16 hoursat room temperature, it is mixed with 2 M hydrochloric acid and ethylacetate, the organic phase is washed neutral with water, dried (Na₂SO₄)and concentrated by evaporation. After chromatography on silica gel withhexane-ethyl acetate (3:2) and recrystallization from diisopropyl ether,80 mg of5-[4-(5-fluoro-2-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]phthalideis obtained, flash point 200-201° C.

6-[4-(5-Fluoro-2-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0462]

[0463] is obtained analogously to Example 4 from4-(5-fluoro-2-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvalericacid and 6-amino-2,3-benzoxazin-1-one, flash point 208-210° C.

EXAMPLE 65-[4-(3-Fluoro-4-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl-amino]phthalide

[0464]4-(3-Fluoro-4-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvalericacid is obtained from4-(3-fluoro-4-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvalericacid-ethyl ester as an oil as described under Example 4 for4-(5-fluoro-2-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvalericacid.

5-[4-(3-Fluoro-4-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl-amino]phthalide

[0465]

[0466] is obtained analogously to Example 4 from4-(3-fluoro-4-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvalericacid and 5-aminophthalide, flash point 188-189° C.

EXAMPLE 76-[4-(3-Fluoro-4-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0467]

[0468] is obtained analogously to Example 4 from4-(3-fluoro-4-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvalericacid and 6-amino-2,3-benzoxazin-1-one, flash point 236-237° C.

EXAMPLE 86-[4-(2-Bromo-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl-amino]-4-methyl-2,3-benzoxazin-1-one

[0469] Precursors

3-Methyl-2-butenoic acid-(4-fluorophenyl)amide

[0470] A solution of 10.0 g (0.1 mol) of 3-methyl-2-butenoic acid in 200ml of THF is mixed with 9.4 ml (0.1 mol) of ethyl chloroformate and 14.1ml (0.1 mol) of triethylamine at 0° C. After 10 minutes at roomtemperature, 10.6 ml (0.11 mol) of 4-fluoroaniline is added to it. Thebatch is stirred for 1 hour at room temperature, diluted with water andextracted with ethyl acetate (1 l). The organic phase is washed withsaturated NaCl, dried (Na₂SO₄) and concentrated by evaporation in avacuum. The residue is purified by column chromatography on silica gelwith hexane-ethyl acetate. Yield 18.8 g.

[0471]¹H-NMR (CDCl₃), δ (ppm)=1.92 (d, 3H), 2.25 (d, 3H), 5.71 (sept,1H), 7.02 (t, 2H), 7.13 (br., 1H), 7.50 (br., 2H).

3,4-Dihydro-4,4-dimethyl-6-fluoro-2-quinolone

[0472] 9.4 g (48.7 mmol) of 3-methyl-2-butenoicacid-(4-fluorophenyl)amide is heated to 130-140° C. and mixed inportions with 9.6 g (73.5 mmol) of aluminum trichloride. After theaddition is completed, the temperature is kept at 80° C. for 30 moreminutes. It is allowed to cool to room temperature and carefully treatedwith 60 ml of ice water. After 150 ml of chloroform is added, the batchis stirred for 15 minutes, acidified with dilute hydrochloric acid andextracted with chloroform (3×150 ml). The combined organic extracts arewashed with saturated NaCl, dried (Na₂SO₄) and concentrated byevaporation in a vacuum. Column chromatography on silica gel withhexane-ethyl acetate yields 6.0 g.

[0473]¹H-NMR (CDCl₃), δ (ppm)=1.34 (s, 6H), 2.48 (s, 2H), 6.80 (dd, 1H),6.88 (td, 1H), 7.02 (dd, 1H), 9.02 (br., 1H).

1-tert-Butoxycarbonyl-3,4-dihydro-4,4-dimethyl-6-fluoro-2-quinolone

[0474] A solution of 6.0 g (30.9 mmol) of3,4-dihydro-4,4-dimethyl-6-fluoro-2-quinolone in 200 ml of THF is mixedwith 8.8 g (40.2 mmol) of di-tert-butyldicarbonate and 4.9 g (40.2 mmol)of DMAP. After 24 hours at room temperature, it is concentrated byevaporation, and the residue is purified by column chromatography onsilica gel with hexane-ethyl acetate. Yield: 9.0 g.

[0475]1H-NMR (CDCl₃), δ (ppm)=1.34 (s, 6H), 1.61 (s, 9H), 2.50 (s, 2H),6.91 (m, 2H), 7.03 (dd, 1H).

3-(2-tert-Butoxycarbonylamino-5-fluorophenyl)-3-methyl-1-butanol

[0476] 375 ml (0.75 mol) of an aqueous 2 M lithium hydroxide solution isadded to a solution of 44 g (0.15 mol) of1-tert-butoxycarbonyl-3,4-dihydro-4,4-dimethyl-6-fluoro-2-quinolone in 1l of THF. After 24 hours at room temperature, the batch is concentratedby evaporation, brought to pH 4 with 10% citric acid and extracted withether. The combined organic extracts are washed with saturated NaCl,dried (Na₂SO₄) and concentrated by evaporation in a vacuum. Columnchromatography of the residue on silica gel with hexane-ethyl acetateyields 34.0 g of3-(2-tert-butoxycarbonylamino-5-fluorophenyl)-3-methylbutyric acid[¹H-NMR (CDCl₃) δ (ppm)=1.62 (br.s, 15 H), 2.77 (s, 2H), 6.41 (br, 1H),6.93 (td, 1H), 7.07 (dd, 1H), 7.20 (br, 1H)], which dissolves in 1 l ofTHF and is mixed at 0° C. with 17 ml (121 mmol) of triethylamine and11.5 ml (121 mmol) of ethyl chloroformate. After 10 minutes at 0° C.,20.7 g (546 mmol) of sodium borohydride is added to it, and 1 l of MeOHis slowly added in drops to it. The batch is stirred for another 30minutes at 0° C., concentrated by evaporation and diluted with ethylacetate. It is washed with saturated NaCl, dried on Na₂SO₄ and purifiedby column chromatography on silica gel with hexane-ethyl acetate. Yield:6.7 g.

[0477]¹H-NMR (CDCl₃), δ (ppm)=1.40 (s, 6H), 1.51 (s, 9H), 2.06 (t, 2H),3.49 (q, 2H), 6.32 (br.s, 1H), 6.91 (ddd, 1H), 7.05 (dd, 1H), 7.28 (br.,1H)

2,2-Dimethylpropionic acid-[3-(2-amino-5-fluorophenyl)-3-methyl]butylester

[0478] A solution of 6.7 g (22.7 mmol) of3-(2-tert-butoxycarbonylamino-5-fluorophenyl)-3-methyl-1-butanol in 200ml of pyridine is mixed at 0° C. with 5.6 ml of pivaloyl chloride. After24 hours at room temperature, water is added to it, and it is stirredfor 2 hours at room temperature. The batch is diluted with ethylacetate, washed with 10% citric acid, water, saturated NaHCO₃ andsaturated NaCl, dried (Na₂SO₄) and concentrated by evaporation in avacuum. Column chromatography on silica gel with hexane-ethyl acetateyields 9.0 g of 2,2-dimethylpropionicacid-[3-(2-tert-butoxycarbonylamino-5-fluorophenyl)-3-methyl]butylester. 6.1 g (16 mmol) of it is dissolved in 100 ml of dichloromethaneand mixed with 30 ml of trifluoroacetic acid. After 30 minutes at roomtemperature, the batch is diluted with ethyl acetate, washed with water,saturated NaHCO₃ and saturated NaCl, dried (Na₂SO₄) and concentrated byevaporation in a vacuum. Purification by column chromatography on silicagel with hexane-ethyl acetate yields 4.0 g of product.

[0479]¹H-NMR (CDCl₃), δ (ppm)=1.15 (s, 9H), 1.46 (s, 6H), 2.15 (t, 2H),3.67 (br, 2H), 3.92 (t, 2H), 6.57 (dd, lH), 6.75 (ddd, 1H), 6.92 (dd,1H).

2,2-Dimethylpropionic acid-[3-(2-bromo-5-fluorophenyl)-3-methyl]butylester

[0480] A solution of 1.9 g (8.5 mmol) of copper(II) bromide and 1.4 ml(7.0 mmol) of tert-butyl nitrite in 10 ml of acetonitrile is heated to65° C. and mixed within 10 minutes with a solution of 2.0 g (7.1 mmol)of 2,2-dimethylpropionic acid-[3-(2-amino-5-fluorophenyl)-3-methyl]butylester in 10 ml of acetonitrile. After 5 minutes at 65° C., it is allowedto cool to room temperature, concentrated by evaporation, and theresidue is purified by column chromatography on silica gel withhexane-ethyl acetate: Yield 1.6 g.

[0481]¹H-NMR (CDCl₃), δ (ppm)=1.12 (s, 9H), 1.52 (s, 6H), 2.41 (t, 2H),3.88 (t, 2H), 6.79 (ddd, 1H), 7.12 (dd, 1H), 7.53 (dd, 1H).

3-(2-Bromo-5-fluorophenyl)-3-methylbutanol

[0482] At −20° C., a solution of 1.97 g (5.7 mmol) of2,2-dimethylpropionic acid-[3-(2-bromo-5-fluorophenyl)-3-methyl]butylester in 20 ml of toluene is mixed with 11.9 ml (14.3 mmol) of a 1.2 Mdiisobutylaluminum hydride-toluene solution. After 30 minutes at −20°C., the batch is cooled to −70° C. and mixed with 4 ml of isopropanoland 6 ml of water. After 2 hours at room temperature, the batch isfiltered, and the filtrate is concentrated by evaporation in a vacuum.Column chromatography on silica gel with hexane-ethyl acetate yields1.25 g of product.

[0483]¹H-NMR (CDCl₃), δ (ppm)=1.52 (s, 6H), 2.37 (t, 2H), 3.45 (q, 2H),6.80 (ddd, 1H), 7.12 (dd, 1H), 7.54 (dd, 1H).

2-[1-Benzoyl-3-(2-bromo-5-fluorophenyl)-3-methylbutyl]furan

[0484] A solution of 1.0 g (3.8 mmol) of3-(2-bromo-5-fluorophenyl)-3-methylbutanol in 24 ml of dichloromethaneis treated with 8.5 ml of DMSO, 2.66 ml (19.2 mmol) of triethylamine and1.23 g (7.7 mmol) of pyridine-sulfur trioxide complex. After 1 hour atroom temperature, the batch is mixed with 30 ml of saturated NH₄Cl, andafter 15 minutes, it is extracted with 400 ml of ether. The extract iswashed with saturated NaCl, dried (Na₂SO₄) and concentrated byevaporation in a vacuum. The residue (1.1 g) is dissolved in 8 ml of THFand added at −70° C. within 30 minutes to a solution of 2-furyllithiumin 38 ml of THF, which is produced from 0.85 ml of furan (11.5 mmol) and7.7 ml (12.3 mmol) of a 1.6 M nBuLi-hexane solution according to A.Dondoni et al., J. Org. Chem. 1997, 62, 5484. After 1.5 hours at −70°C., the batch is poured into 50 ml of saturated NH₄Cl and extracted with400 ml of MTBE. The organic phase is dried (Na₂SO₄) and concentrated byevaporation in a vacuum. The residue (1.1 g) is dissolved in 40 ml ofpyridine and mixed first with 0.9 ml (7.7 mmol) of benzoyl chloride at0° C. After 2 hours at 0° C. and 2 hours at room temperature, 30 mg ofDMAP is added to it, and after another 2 hours at room temperature, afurther 0.9 ml (7.7 mmol) of benzoyl chloride. After 18 hours at roomtemperature, the batch is mixed with 3 ml of water and concentrated byevaporation in a vacuum. The residue is taken up in 400 ml of MTBE, andthe resulting solution is washed with 10% citric acid and saturatedNaCl, dried (Na₂SO₄) and concentrated by evaporation in a vacuum. Columnchromatography on silica gel with hexane-ethyl acetate yields 1.46 g ofproduct.

[0485]¹H-NMR (CDCl₃), δ (ppm)=1.52 (s, 3H), 1.58 (s, 3H), 2.53 (dd, 1H),3.33 (dd, 1H), 6.10 (dd, 1H), 6.26 (m, 2H), 6.49 (ddd, 1H), 6.97 (dd,1H), 7.34 (m, 4H), 7.48 (m, 1H), 7.81 (m, 2H).

2-Benzoyl-4-(2-bromo-5-fluorophenyl)-4-methylvaleric acid-methyl ester

[0486] A suspension of 10.9 g (50.8 mmol) of sodium periodate in 140 mlof water-acetonitrile-tetrachloromethane (4:2:1) is mixed with 45 mg(0.34 mmol) of ruthenium(IV)oxide-hydrate. After 10 minutes, a solutionof 2-[1-benzoyl-3-(2-bromo-5-fluorophenyl)-3-methylbutyl]furan in 40 mlof acetonitrile is added to it, it is stirred for another 10 minutes,and the batch is poured into 400 ml of saturated Na₂SO₃. A pH of 5 isset with 10% citric acid, and the batch is extracted with ethyl acetate.The combined extracts are dried (Na₂SO₄) and concentrated by evaporationin a vacuum. The residue is taken up in 8 ml of DMF and treated with0.42 ml (6.8 mmol) of methyl iodide and 2.21 g (6.8 mmol) of cesiumcarbonate. After 5 hours at room temperature, the batch is diluted with600 ml of MTBE, washed with 10% sulfuric acid and saturated NaCl, dried(Na₂SO₄) and concentrated by evaporation in a vacuum. Columnchromatography on silica gel with hexane-ethyl acetate yields 0.9 g ofproduct.

[0487]¹H-NMR (CDCl₃), δ (ppm)=1.58 (s, 3H), 1.62 (s, 3H), 2.55 (dd, 1H),3.10 (dd, 1H), 3.72 (s, 3H), 5.21 (dd, 1H), 6.58 (ddd, 1H), 7.03 (dd,1H), 7.35-7.47 (m, 3H), 7.55 (m, 1H), 7.83 (m, 2H).

4-(2-Bromo-5-fluorophenyl)-2-hydroxy-4-methylvaleric acid-methyl ester

[0488] A solution of 0.9 g (2.13 mmol) of2-benzoyl-4-(2-bromo-5-fluorophenyl)-4-methylvaleric acid-methyl esterin 50 ml of MeOH is mixed with 1.47 g (10.6 mmol) of potassium carbonateand stirred for 3 hours at room temperature. The batch is acidified (pH3) with 10% sulfuric acid, and it is extracted with ethyl acetate. Thecombined extracts are washed with saturated NaCl, dried (Na₂SO₄) andconcentrated by evaporation in a vacuum. The residue is taken up in 8 mlof DMF and stirred with 1.92 g (5.9 mmol) of cesium carbonate and 0.38ml (5.9 mmol) of methyl iodide for 3 hours at room temperature. Thebatch is mixed with 10% citric acid and extracted with MTBE. The organicphase is washed with saturated NaCl, dried (Na₂SO₄) and concentrated byevaporation in a vacuum. Column chromatography on silica gel withhexane-ethyl acetate yields 250 mg of product.

[0489]¹H-NMR (CDCl₃), δ (ppm)=1.57 (s, 3H), 1.61 (s, 3H), 2.10 (dd, 1H),2.51 (d, 1H), 2.82 (dd, 1H), 3.74 (s, 3H), 3.96 (ddd, 1H), 6.81 (ddd,1H), 7.22 (dd, 1H), 7.55 (dd, 2H).

6-[4-(2-Bromo-5-fluorophenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0490] 663 mg (1.56 mol) of1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one(Dess-Martin-periodinane, cf. D. B. Dess, J. C. Martin, J. Am. Chem.Soc. 1991, 113, 7277) is added to a solution of 250 mg (0.78 mmol) of4-(2-bromo-5-fluorophenyl)-2-hydroxy-4-methylvaleric acid-methyl esterin 10 ml of dichloromethane. After 1.5 hours at room temperature, thebatch is diluted with 150 ml of MTBE, washed with a solution of 1.2 g ofNaHCO₃ and 4.0 g of Na₂SO₃ in 50 ml of water, saturated NaHCO₃ andsaturated NaCl, dried (Na₂SO₄) and concentrated by evaporation in avacuum. The residue (250 mg) is taken up in 16 ml of THF-EtOH (1:1) andmixed with 3.9 ml (3.9 mmol) of a 1 M sodium hydroxide solution. After30 minutes, the batch is concentrated in a vacuum, diluted with 20 ml ofwater and washed with MTBE. The aqueous phase is acidified with 10%sulfuric acid (pH 2) and extracted with 100 ml of ethyl acetate and 100ml of dichloromethane. The combined extracts are dried (NaSO₄) andconcentrated by evaporation in a vacuum. 0.06 ml (0.92 mmol) of thionylchloride is added in drops at −6° C. to the solution of the residue (230mg) in 5 ml of dimethyl acetamide. After 20 minutes at −6° C., 201 mg(1.14 mmol) of 6-amino-4-methyl-2,3-benzoxazin-1-one is added to it. Thebatch is stirred for 15 hours at room temperature, acidified with 50 mlof 10% citric acid and shaken out with 150 ml of MTBE. The organic phaseis washed with saturated NaCl, dried (Na₂SO₄) and concentrated byevaporation in a vacuum. Column chromatography on silica gel withhexane-ethyl acetate yields 290 mg of product.

[0491]¹H-NMR ([D₆]-DMSO), δ (ppm)=1.57 (s, 6H), −2.5 (s, 3H; under theDMSO signal), 3.89 (s, 2H), 7.03 (ddd, 1H), 7.34 (dd, 1H), 7.62 (dd,1H), 8.25 (d, 1H), 8.33 (m, 2H), 11.03 (br., 1H);

[0492] MS (Cl) m/z=461, 463 (M⁺)

6-[4-(2-Bromo-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0493]

[0494] 0.23 ml (1.25 mmol) of trifluoromethyl(trimethyl)silane and 256mg (0.79 mmol) of cesium carbonate are added at 0° C. to a solution of290 mg (0.63 mmol) of6-[4-(2-bromo-5-fluorophenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-onein 7 ml of DMF. After 24 hours, the same amount of silane and base areadded and stirred for another 24 hours at room temperature. The batch isdiluted with 150 ml of ethyl acetate, washed with water and saturatedNaCl, dried (Na₂SO₄) and concentrated by evaporation in a vacuum.Purification by column chromatography of the residue on silica gelyields 230 mg of product.

[0495]¹H-NMR (CDCl₃), δ (ppm)=1.55 (s, 3H), 1.63 (s, 3H), 2.58 (s, 3H),3.10 (br. s, 1H), 6.63 (ddd, 1H), 7.11 (dd, 1H), 7.40 (dd, 1H), 7.62(dd, 1H), 8.14 (d, 1H), 8.33 (d, 1H), 8.52 (br.s, 1H);

[0496] MS (Cl) m/z=531, 533 (M⁺)

EXAMPLE 96-[4-(Indan-4′-yl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0497] Precursors

4-(1-Hydroxy-1-methylethyl)indane

[0498] 10 ml (14 mmol) of a 1.4 M methylmagnesium bromide solution intoluene-THF (3:1) is added in drops at 0° C. to a solution of 1.6 g (10mmol) of 4-acetylindane (F. Dallacker, J. Van Wersch, Chem. Ber. 1972,105, 2565) in 40 ml of THF. After 30 minutes at 0° C. and 1.5 hours atroom temperature, the batch is diluted with 200 ml of ethyl acetate,washed with 1 M hydrochloric acid and saturated NaCl, dried (Na₂SO₄) andconcentrated by evaporation in a vacuum. Column chromatography of theresidue on silica gel with hexane-ethyl acetate yields 0.64 g ofproduct.

[0499]¹H-NMR (CDCl₃), δ (ppm)=1.64 (s, 6H), 1.74 (s, 1H), 2.07 (pent,2H), 2.90 (t, 2H), 3.16 (t, 2H), 7.11-7.19 (m, 2H), 7.29 (m, 1H).

6-[4-(Indan-4′-yl)-4-methyl-2-oxovaleric acid

[0500] 0.63 g (3.4 mmol) of 4-{1-hydroxy-1-methylethyl)indane isintroduced with 0.96 g (5.1 mmol) of 2-trimethylsiloxyacrylic acid-ethylester (H. Sugimura, K. Yoshida, Bull. Chem. Soc. Jpn. 1992, 65, 3209)into 20 ml of dichloromethane and treated at −70° C. with 0.31 ml (2.6mmol) of tin(IV) chloride. After 20 minutes at −70° C., the batch ispoured into semiconcentrated potassium carbonate solution and extractedwith ethyl acetate. The combined extracts are washed with saturatedNaCl, dried (Na₂SO₄) and concentrated by evaporation in a vacuum. 0.89 gof an oil, which is dissolved in 30 ml of EtOH-THF (2:1) and is reactedwith 12.8 ml (12.8 mmol) of 1 M NaOH, is obtained. After 2 hours at roomtemperature, the batch is concentrated by evaporation in a vacuum, andthe residue is taken up in 30 ml of water. The aqueous phase is washedwith ether and acidified with 50 ml of 1 M hydrochloric acid. Extractionwith ethyl acetate, drying (Na₂SO₄) and concentration by evaporationyields 0.64 g of acid.

[0501]¹H-NMR (CDCl₃), δ (ppm)=1.52 (s, 6H), 2.07 (pent, 2H), 2.85 (t,2H), 3.08 (t, 2H), 3.42 (s, 2H), 5.02 (br.), 7.04-7.17 (m, 3H).

6-[4-(Indan-4′-yl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0502] 0.63 g (2.6 mmol) of 6-[4-(indan-4′-yl)-4-methyl-2-oxovalericacid and 0.69 g (3.9 mmol) of 6-amino-4-methyl-2,3-benzoxazin-1-one areconverted into 0.31 g of product as described in Example 1.

[0503]¹H-NMR (CDCl₃), δ (ppm)=1.56 (s, 6H), 2.08 (pent, 2H), 2.59 (s,3H), 2.83 (t, 2H), 3.12 (t, 2H), 3.52 (s, 2H), 7.07-7.17 (m, 3H), 7.72(dd, 1H), 8.20 (d, 1H), 8.36 (d, 1H), 8.87 (br. s, 1H).

6-[4-(Indan-4′-yl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0504]

[0505] In a way similar to the instructions of Example 1, 0.31 g (0.77mmol) of6-[4-(indan-4′-yl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-oneis reacted with 0.56 ml (3.1 mol) of trifluoromethyl(trimethyl)silaneand 626 mg (1.9 mmol) of cesium carbonate in 9 ml of DMF. After columnchromatography on silica gel with hexane-ethyl acetate, 90 mg of productis obtained.

[0506]¹H-NMR (CDCl₃), δ (ppm)=1.47 (s, 3H), 1.49 (s, 3H), 2.11 (m, 2H),2.62 (s, 3H), 2.76-2.92 (m, 4H), 2.96 (s, 1H), 3.17 (t, 2H), 7.14 (m,4H), 7.63 (dd, 1H), 8.28 (d, 1H), 8.35 (d, 1H), 8.88 (br. s, 1H);

[0507] MS (Cl) m/z=475 (MH⁺).

[0508] Separation of Enantiomers of Example 9

[0509] The enantiomer mixture of Example 9 is separated bychromatography on chiral support medium (CHIRALPAK AD®, DAICEL Company)with hexane/ethanol (95:5, vv). Thus obtained from 830 mg of racemateare:

[0510] (−)6-[4-(Indan-4′-yl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-oneas a first fraction: 310 mg, [MS (Cl) m/z=475 (MH⁺), α_(D)=−55.7° (c=0.5in tetrahydrofuran)] and

[0511] (+)6-[4-(Indan-4′-yl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-oneas a second fraction: 280 mg, [Flash point 196-197° C., α_(D)=+55.7°(c=0.5 in tetrahydrofuran)]

EXAMPLE 106-[4-(5-Fluoro-2-vinylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one2-Benzoyl-4-(5-fluoro-2-vinylphenyl)-4-methylvaleric acid-methyl ester

[0512] A solution of 0.53 g (1.25 mmol) of2-benzoyl-4-(2-bromo-5-fluorophenyl)-4-methylvaleric acid-methyl esterand 77 mg (0.07 mmol) of tetrakis(triphenylphosphine)palladium in 40 mlof toluene is refluxed with vinyl(tributyl)stannane for 8 hours. Then,it is concentrated by evaporation and purified by column chromatographyon silica gel with hexane-ethyl acetate: 320 mg of product.

[0513]¹H-NMR (CDCl₃), δ (ppm)=1.51 (s, 3H), 1.55 (s, 3H), 2.44 (dd, 1H),2.66 (dd, 1H), 3.70 (s, 3H), 5.14 (dd, 1H), 5.33 (dd, 1H), 5.43 (dd,1H), 6.77 (td, 1H), 6.97 (dd, 1H), 7.22-7.33 (m, 2H), 7.48 (m, 2H), 7.55(m, 1H), 7.80 (d, 2H).

4-(5-Fluoro-2-vinylphenyl)-2-hydroxy-4-methylvaleric acid-methyl ester

[0514] Produced analogously to Example 8.

[0515]¹H-NMR (CDCl₃), δ (ppm)=1.48 (s, 3H), 1.53 (s, 3H), 1.98 (dd, 1H),2.46 (dd, 1H), 2.50 (d, 1H), 3.70 (s, 3H), 3.96 (ddd, 1H), 5.28 (dd,1H), 5.41 (dd, 1H), 6.90 (td, 1H), 7.12 (dd, 1H), 7.25 (dd, 1H), 7.33(dd, 1H).

6-[4-(5-Fluoro-2-vinylphenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0516] Produced analogously to Example 8.

[0517]¹H-NMR (CDCl₃), δ (ppm)=1.56 (s, 6H), 2.58 (s, 3H), 3.65 (s, 2H),5.28 (dd, 1H), 5.34 (dd, 1H), 6.91 (td, 1H), 7.13 (dd, 1H), 7.20-7.30(m, 2H), 7.78 (dd, 1H), 8.22 (d, 1H), 8.35 (d, 1H), 8.98 (br., 1H).

6-[4-(5-Fluoro-2-vinylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0518]

[0519] Produced analogously to Example 8.

[0520]¹H-NMR (CDCl₃), δ (ppm)=1.47 (s, 3H), 1.54 (s, 3H), 2.60 (s, 3H),2.87 (m, 3H), 5.45 (dd, 1H), 5.50 (dd, 1H), 6.85 (td, 1H), 7.06 (dd,1H), 7.25-7.37 (m, 2H), 7.67 (dd, 1H), 8.18 (d, 1H), 8.34 (d, 1H), 8.73(br.s, 1H);

[0521] MS (ES+) m/z=479 (MH⁺)

EXAMPLE 116-[2-Hydroxy-4-methyl-2-trifluoromethyl-4-(4-trifluoromethylphenyl)-valeroylamino]-4-methyl-2,3-benzoxazin-1-one2-Methyl-2-(4-trifluomethylphenyl)propionitrile

[0522] A solution of 6.80 g (41.4 mmol) of 4-fluorobenzotrifluoride in250 m of toluene is mixed at 0° C. with 124 ml (62 mmol) of a 0.5 Mpotassium hexamethyldisilazide-THF solution and 9.44 g (137 mmol) ofisobutyric acid nitrile. The batch is stirred for 4 hours at 60° C. anddiluted after cooling with water and ethyl acetate. The organic phase isseparated, washed with 10% H₂SO₄ and saturated NaCl, dried (Na₂SO₄) andconcentrated by evaporation in a vacuum.

[0523] Column chromatography on silica gel with hexane-ethyl acetateyields 7.68 g of product.

[0524]¹H-NMR (CDCl₃) δ (ppm)=1.76 (s, 6H), 7.62 (d, 2H), 7.68 (d, 2H).

4-Methyl-4-(4-trifluomethylphenyl)-2-pentenoic acid-ethyl ester

[0525] A solution of 7.6 g (36 mmol) of2-methyl-2-(4-trifluomethylphenyl)propionitrile in 250 ml of toluene ismixed at −70° C. with 57 ml (68 mmol) of a 1.2 M diisobutylaluminumhydride-toluene solution. After 1 hour at −70° C., 10% tartaric acid isadded in drops to it, and it is stirred for 15 minutes at roomtemperature. The batch is diluted with ether, the organic phase isseparated and washed with saturated NaCl, dried (Na₂SO₄) andconcentrated by evaporation in a vacuum: 7.96 g of crude2-methyl-2-(4-trifluomethylphenyl)propionaldehyde. 2.05 g (9.25 mmol)thereof is dissolved in 6 ml of DME and added in drops to a solutionthat was prepared from 3.10 g (13.9 mmol) of phosphonoaceticacid-triethyl ester and 0.55 g (13.9 mmol) of 60% sodium hydride in 12ml of DME. After 1 hour at room temperature, the batch is mixed withsaturated NH₄Cl and diluted with ethyl acetate and water. The phases areseparated, the aqueous phase is extracted with ethyl acetate, and thecombined organic extracts are washed with saturated NaCl, dried (Na₂SO₄)and concentrated by evaporation in a vacuum. The residue is purified onsilica gel with hexane-ethyl acetate: 1.72 g of product.

[0526]¹H-NMR (CDCl₃), δ (ppm)=1.30 (t, 3H), 1.49 (s, 6H), 4.21 (q, 2H),5.82 (d, 1H), 7.10 (d, 1H), 7.43 (d, 2H), 7.59 (d, 2H).

2-Hydroxy-4-methyl-4-(4-trifluoromethylphenyl)valeric acid-ethyl ester

[0527] 1.72 g (6.0 mmol) of4-methyl-4-(4-trifluomethylphenyl)-2-pentenoic acid-ethyl ester isstirred in ethyl acetate in the presence of 0.17 g of 10%palladium/activated carbon catalyst for 15 hours in a hydrogenatmosphere (1 atm). The batch is filtered on Celite and concentrated byevaporation in a vacuum: 1.72 g of4-methyl-4-(4-trifluomethylphenyl)valeric acid-ethyl ester. 0.57 g (2.0mmol) thereof is dissolved in 7 ml of THF and treated at −78° C. with5.6 ml (2.8 mmol) of potassium hexamethyldisilazide-toluene solution.After 25 minutes, 0.73 g (2.8 mmol) of3-phenyl-2-phenylsulfonyloxaziridine (F. A. Davis, S. Chattopadhyay, J.C. Towson, S. Lal, T. Reddy J. Org. Chem. 1988, 53, 2087) in 7 ml of THFis added in drops to it and stirred for 30 minutes at −78° C. The batchis mixed with saturated NH₄Cl and heated within 1 hour to roomtemperature. THF is removed in a vacuum, the residue is taken up inether, the solid is filtered off, the phases are separated, and theaqueous phase is extracted with ether. The combined organic extracts arewashed with saturated NaCl, dried (Na₂SO₄) and concentrated byevaporation in a vacuum. Column chromatography on silica gel withhexane-ethyl acetate yields 0.14 g of product.

[0528] 1H-NMR (CDCl₃), δ (ppm)=1.26 (t, 3H), 1.42 (s, 3H), 1.50 (s, 3H),1.90 (dd, 1H), 2.10 (br., 1H), 2.24 (dd, 1H), 3.94 (dd, 1H), 4.15 (m,2H), 7.53 (d, 2H), 7.60 (d, 2H).

6-[4-Methyl-2-oxo-4-(4-trifluoromethylphenyl)-valeroylamino]-4-methyl-2,3-benzoxazin-1-one

[0529] Produced analogously to Example 8.

[0530]¹H-NMR (CDCl₃), δ (ppm)=1.53 (s, 6H), 2.58 (s, 3H), 3.47 (s, 2H),7.50 (d, 2H), 7.58 (d, 2H), 7.78 (dd, 1H), 8.21 (d, 1H), 8.35 (d, 1H),8.98 (br., 1H);

[0531] MS (Cl) m/z=433 (MH⁺)

6-[2-Hydroxy-4-methyl-2-trifluoromethyl-4-(4-trifluoromethylphenyl)-valeroyl-amino]-4-methyl-2,3-benzoxazin-1-one

[0532]

[0533] Produced analogously to Example 8.

[0534]¹H-NMR (CDCl₃), δ (ppm)=1.47 (s, 3H), 1.50 (s, 3H), 2.53 (d, 1H),2.58 (s, 3H), 2.91 (s, 1H ), 2.95 (d, 1H), 7.55 (s, 4H), 7.62 (dd, 1H),8.18 (d, 1H), 8.33 (d, 1H), 8.73 (br.s, 1H);

[0535] MS (ES+) m/z=503 (MH⁺).

EXAMPLE 126-[4-(2-Bromo-3,5-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0536]

[0537] Produced analogously to Example 8.

[0538]¹H-NMR (CDCl₃), δ (ppm)=1.56 (s, 3H), 1.64 (s, 3H), 2.58 (s, 3H),3.00 (d, 1H), 3.22 (d, 1H), 3.31 (br. s, 1H), 6.58 (td, 1H), 6.97 (dt,1H), 7.64 (dd, 1H), 8.11 (d, 1H), 8.34 (d, 1H), 8.43 (br.s, 1H).

EXAMPLE 136-[4-(3,5-Difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0539]

[0540] Example 13 accumulates as by-product in the synthesis of Example12.

[0541]¹H-NMR (CDCl₃), δ (ppm)=1.41 (s, 3H), 1.44 (s, 3H), 2.44 (d, 1H),2.60 (s, 3H), 2.80 (br. s, 1H), 2.89 (d, 1H), 6.53 (tt, 1H), 6.92 (m,2H), 7.66 (dd, 1H), 8.24 (d, 1H), 8.35 (d, 1H), 8.70 (br.s, 1H).

EXAMPLE 146-[4-(5-Fluoro-2-trifluoromethylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one2-(5-Fluoro-2-trifluoromethylphenyl)-acetonitrile

[0542] 1.95 g (30 mmol) of potassium cyanide is added to a solution of5.14 g (20 mmol) of 5-fluoro-2-trifluoromethylbenzyl bromide in 45 ml ofethanol/8 ml of water, and it is stirred for 64 hours at roomtemperature. The reaction solution is diluted with ethyl acetate andextracted with saturated sodium bicarbonate solution. The organic phaseis washed with water, dried and concentrated by evaporation. Theremaining residue is purified by bulb tube distillation andrecrystallized. Yield: 3.6 g (89%).

[0543] Flash point 41-42° C.

2-(5-Fluoro-2-trifluoromethylphenyl)-2-methyl-propionitrile

[0544] Analogously to the process that is described for2-(5-fluoro-2-methylphenyl)-2-methylpropionitrile,2-(5-fluoro-2-trifluoromethylphenyl)-2-methyl-propionitrile is obtainedas a colorless oil, boiling point 90° C./0.04 hPa.

2-(5-Fluoro-2-trifluoromethylphenyl)-2-methyl-propionaldehyde

[0545] Analogously to the process that is described for2-(5-fluoro-2-methylphenyl)-2-methylpropionaldehyde,2-(5-fluoro-2-trifluoromethylphenyl)-2-methyl-propionaldehyde isobtained as a colorless oil, boiling point 80° C./0.05 hPa.

4-(5-Fluoro-2-trifluoromethylphenyl)-4-methyl-oxovaleric acid

[0546] Analogously to the process that is described for4-(5-fluoro-2-methylphenyl)-4-methyl-oxovaleric acid,4-(5-fluoro-2-trifluoromethylphenyl)-4-methyl-oxovaleric acid isobtained as a viscous oil.

6-[4-(5-Fluoro-2-trifluoromethylphenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0547] Analogously to the process that is described for6-[4-(5-fluoro-2-methylphenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-one,6-[4-(5-fluoro-2-trifluoromethylphenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-oneis synthesized.

[0548]¹H-NMR (CDCl₃+DMSO), δ (ppm)=1.47 (s, 6H), 2.44 (s, 3H), 3.59 (s,2H), 6.92 (dt, 1H), 7.33 (dd, 1H), 7.61 (dd, 1H), 8.03 (dd, 1H), 8.16(d, 1H), 8.30 (d, 1H), 10.34 (bs, 1H).

6-[4-(5-Fluoro-2-trifluoromethylphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one

[0549]

[0550] Analogously to the process that is described for6-[4-(5-fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one,6-[4-(5-fluoro-2-trifluoromethylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-oneis synthesized.

[0551]¹H-NMR (CDCl₃) δ (ppm)=1.42 (s, 3H), 1.55 (s, 3H), 2.56 (d, 1H),2.57 (s, 3H), 2.91 (d, 1H), 3.28 (bs, 1H), 6.85 (dt, 1H), 7.32 (dd, 1H),7.56-7.66 (m, 2H), 8.13 (d, 1H), 8.34 (d, 1H), 8.51 (bs, 1H);

[0552] MS (El) m/z=520 (M⁺).

[0553] Separation of the Enantiomers of Example 14

[0554] The enantiomer mixture of Example 14 is separated bychromatography on chiral support medium (CHIRALPAK AD®, DAICEL Company)with hexane/ethanol (19:1, vv). Thus obtained from 100 mg of racemateare:

[0555](−)-6-[4-(5-Fluoro-2-trifluoromethylphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-oneas a first fraction: 40 mg, [flash point 162-165° C., α_(D)=−45.5°(c=0.5 in tetrahydrofuran)] and

[0556](+)-6-[4-(5-Fluoro-2-trifluoromethylphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-oneas a second fraction: 38 mg, [flash point 160-165° C.]

[0557] Analogously to Example 14, the compounds of Table 4 are d.

[0558] Trifluoromethyl Compounds TABLE 4

Com- Flash point Isomerism or pound R5 R6 R7 R8 R1/R2 [° C.] [α]_(D) 1 HH H H CH₃ 154-156 racemate 2 H H H H CH₃ 164-170 −72.8 3 H H H H CH₃188-190 +69.0 4 H F H H CH₃ 170-172 racemate 5 H F H H CH₃ 173-175 −67.56 H F H H CH₃ 174-177 (+)-form 7 H H F H CH₃ 170 racemate 8 H H F H CH₃162-166 −45.5 9 H H F H CH₃ 160-165 (+)-form 10 H H Cl H CH₃ 172racemate 11 H H Cl H CH₃ 178-181 −143.1 12 H H Cl H CH₃ 180-182 (+)-form

EXAMPLE 156-hydroxy-4-methyl-2-trifluoromethyl-4-(1-naphthyl)-valeroylamino]-4-methyl-2,3-benzoxazin-1-one2-Methyl-2-(1-naphthyl)-propionitrile

[0559] A solution of 16.7 g (100 mmol) of 1-naphthylacetonitrile in 200m of DMF and 15 ml (240 mmol) of methyl iodide is mixed at 0° C. with10.4 g (260 mmol) of sodium hydride (addition within 2.5 hours). Thebatch is stirred for 3 hours at 0° C. and for 18 hours at 25° C. It ismixed with ice and ethyl acetate. The organic phase is acidified with10% H₂SO₄₁ washed three times with water, dried (Na₂SO₄) andconcentrated by evaporation in a vacuum. A large-scale purification iscarried out by bulb tube distillation (boiling range 60-130° C.) in anoil pump vacuum; yield: 18.8 g.

[0560]¹H-NMR (CDCl₃), δ (ppm)=2.00 (s, 6H), 7.41-7.60 (m, 3H), (ddd,1H), 7.87 (d br., 1H), 7.93 (dd, 1H), 8.55 (d, 1H).

4-Methyl-4-(1-naphthyl)-2-pentenoic acid-ethyl ester

[0561] Analogously to the production of4-methyl-4-(4-trifluomethylphenyl)-2-pentenoic acid-ethyl ester ofExample 11, 7.62 g of the product is obtained from 8.81 g (45.1 mmol) of2-methyl-2-(1-naphthyl)-propionitrile.

[0562]¹H-NMR (CDCl₃), δ (ppm)=1.25 (t, 3H), 1.70 (s, 6H), 4.16 (q, 2H),5.73 (d, 1H), 7.38-7.50 (m, 4H), 7.53 (dd, 1H), 7.78 (d, 1H), 7.81-7.89(m, 1H), 8.00-8.08 (m, 1H).

2-Hydroxy-4-methyl-4-(1-naphthyl)-valeric acid-ethyl ester

[0563] Analogously to the production of2-hydroxy-4-methyl-4-(4-trifluomethylphenyl)-valeric acid-ethyl ester ofExample 11, 3.52 g of the product is obtained from 7.62 g (28.4 mmol) of4-methyl-4-(1-naphthyl)-2-pentenoic acid-ethyl ester.

[0564]¹H-NMR (CDCl₃), δ (ppm)=1.14 (t, 3H), 1.72 (s, 3H), 1.74 (s, 3H),2.27 (dd, 1H), 2.52 (dd, 1H), 2.76 (dd, 1H), 3.95-4.08 (m, 3H),7.38-7.51 (m, 3H), 7.57 (d, 1H), 7.75 (d, 1H), 7.88 (dd, 1H), 8.40 (d,1H).

6-[4-Methyl-2-oxo-4-(1-naphthyl)-valeroylamino]-4-methyl-2,3-benzoxazin-1-one

[0565] Produced analogously to Example 11. 861 mg of the product isobtained.

[0566]¹H-NMR (CDCl₃), δ (ppm)=1.59 (s, 3H), 1.78 (s, 6H), 2.57 (s, 3H),3.88 (s, 2H), 7.44 (m, 2H), 7.54 (m, 2H), 7.69 (dd, 1H), 7.75 (d br.,1H), 7.87 (dd, 1H), 8.15 (d, 1H), 8.32 (d, 1H), 8.46 (d br., 1H).

6-[2-Hydroxy-4-methyl-2-trifluoromethyl-4-(1-naphthyl)-valeroylamino]-4-methyl-2,3-benzoxazin-1-one

[0567]

[0568] Produced analogously to Example 8. 77.1 mg of the product isobtained.

[0569]¹H-NMR (CDCl₃), δ (ppm)=1.57 (s, 3H), 1.67 (s, 3H), 1.78 (s, 3H),2.54 (s, 2H), 3.10 (d, 1H), 3.23 (d, 1H), 5.30 (s, 2H), 7.25-7.38 (m,2H), 7.46 (dd, 1H), 7.51 (d, 1H), 7.60 (m, 2H), 7.76 (d, 1H), 7.97 (dbr., 1H), 8.24 (d, 1H), 8.42 (d, 1H).

EXAMPLE 166-[3-{1-(2-Chlorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one

[0570] Precursors

1-(2-Chlorophenyl)-cyclopropane-carbonitrile

[0571] A solution of 13.1 g of 2-chlorophenylacetonitrile and 20.3 g of1,2-dibromopropane in 142 ml of DMF is mixed with 9 g of sodium hydride[55-65% in oil] at room temperature. It is stirred for several hours andcarefully added to water. After extraction with ethyl acetate andfiltration by silica gel, the desired product is obtained: 13.1 g

[0572] MS (ei): M⁽⁺⁾=177

1-(2-Chlorophenyl)-1-cyclopropane carbaldehyde

[0573] 13.1 g of (1-(2-chlorophenyl)-1-cyclopropane carbaldehyde in 116ml of toluene is mixed at −70° C. drop by drop with 64.5 ml ofdiisobutylaluminum hydride. After 4 hours at −70° C., 343 ml of ethylacetate is added. It is allowed to come to room temperature overnight.Water and ethyl acetate are added, filtered on diatomaceous earth, ethylacetate solution is washed with water, dried (Na₂SO₄) and concentratedby evaporation. After flash chromatography on silica gel withhexane-ethyl acetate (8:2), 9.7 g of the product is obtained.

[0574] MS (ei): M⁽⁺⁾=−180

2-Ethoxy-3-[1-(2-chlorophenyl)-1-cyclopropyl]-acrylic acid ethyl ester

[0575] 14.3 g of phosphonate in 40 ml of tetrahydrofuran is mixed at 0°C. with 29 ml of lithium diisopropylamide. It is stirred for 20 moreminutes at 0° C. 9.7 g of 1-(2-chlorophenyl)-1-cyclopropane carbaldehydein 40 ml of tetrahydrofuran is added in drops. After 24 hours at roomtemperature, it is mixed with water, extracted with ethyl acetate, ethylacetate solution is washed with water and dried (Na₂SO₄). Afterconcentration by evaporation, 15.5 g of the product is obtained.

[0576] MS (ei): M⁽⁺⁾=294

2-Ethoxy-3-[1-(2-chlorophenyl)-1-cyclopropyl]-acrylic acid

[0577] 15.4 g of 2-ethoxy-3-[1-(2-chlorophenyl)-1-cyclopropyl]-acrylicacid ethyl ester in 350 ml of 1 M sodium hydroxide solution(ethanol-water 2:1) is stirred for 24 hours at room temperature. Solventis distilled off, residue is distributed between water and diethylether, water solution is acidified with 2N hydrochloric acid, andextracted with diethyl ether. After the organic phase is washed withwater, dried (Na2SO4) and concentrated by evaporation, 11.2 g of theproduct is obtained.

[0578] MS (ei): M⁽⁺⁾=266

3-[1-(2-Chlorophenyl)-1-cyclopropyl]-2-oxo-propionic acid

[0579] 11.2 g of 2-ethoxy-3-[1-(2-chlorophenyl)-1-cyclopropyl]-acrylicacid is stirred in 230 ml of 1 M sulfuric acid and 42 ml of concentratedacetic acid for 24 hours at 110° C. Water is added, it is extracted withethyl acetate, and ethyl acetate solution is washed with water. Afterdrying (Na2SO4) and concentration by evaporation, 10.7 g of the productis obtained.

[0580] MS (ei): M⁽⁺⁾=238

[0581]¹H-NMR (CDCl₃), a (ppm)=0.98 (m, 4H), 3.28 (s, 2H), 7.13-7.22 (m,2H), 7.29-7.35 (m, 1H), 7.43-7.49 (m, 1H)

6-{3-[1-(2-Chlorophenyl)-cyclopropyl]-2-oxopropionylamino}-4-methyl-2,3-benzoxazin-1-one

[0582] 10.7 g of 3-[1-(2-chlorophenyl)-1-cyclopropyl]-2-oxopropionicacid in 175 ml of dimethyl acetamide is mixed at −5° C. with 4.1 ml ofthionyl chloride, and it is stirred for 20 minutes. Then, 5.0 g of MBOis added in solid form. After 20 hours at room temperature, water andethyl acetate are added, ethyl acetate solution is washed with water,dried (Na2SO4) and concentrated by evaporation. After chromatography onsilica gel with hexane-ethyl acetate (0%-30%), 9.6 g of the product isobtained.

[0583] MS (ei) M⁽⁺⁾=397

6-{3-[1-(2-Chlorophenyl)-cyclopropyl]-2-hydroxy-2-trifluoromethylpropionylamino}-4-methyl-2,3-benzoxazin-1-one

[0584] 9.5 g of6-{3-[1-(2-chlorophenyl)-cyclopropyl]-2-oxopropionylamino}-4-methyl-2,3-benzoxazin-1-onein 140 ml of dimethylformamide is mixed at 0° C. with 16.9 ml oftrifluoromethyl-trimethylsilane and 9.65 g of cesium carbonate. After 24hours at room temperature, a spatula tip full of tetrabutylammoniumfluoride hydrate is added, and it is stirred for 30 more minutes. It ismixed with water and ethyl acetate, ethyl acetate solution is washedwith water, dried (Na2SO4) and concentrated by evaporation. Afterchromatography on silica gel with hexane-ethyl acetate (0%-30%), 2.98 gof the product is obtained.

[0585] Flash point 195-196° C.

[0586] Separation of the Enantiomers of Example 16

[0587] The enantiomer mixture of Example 16 is separated bychromatography on chiral support medium (CHIRALPAK AD®, DAICEL Company)with hexane/ethanol. Thus obtained from 2.68 g of racemate are:

[0588](−)-6-[3-{1-(2-Chlorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-oneas a first fraction: 1.3 g, [flash point 233-235° C., α_(D)=−81.4°(c=0.5 in chloroform)] and

[0589](+)-6-[3-{1-(2-Chlorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-oneas a second fraction: 1.25 g, [flash point 238-240° C.]

[0590] Analogously to Example 16, the compounds of Tables 5-8 areobtained.

[0591] Chlorine Compounds TABLE 5

Com- Flash point Isomerism or pound R5 R6 R7 R8 n = [° C.] [α]_(D) 1 H HH H 2 231-233 −47.1 2 H H H H 2 230-232 (+)-form 3 H H H H 3 195-197−70.5 4 H H H H 3 202-203 (+)-form 5 H F H H 1 228-230 racemate 6 H F HH 1 218-219 −88.6 7 H F H H 1 217-219 (+)-form 8 H F H H 2 212-214racemate 9 H F H H 2 236-238 +74.2 10 H F H H 2 235-237 −75.0 11 H H F H1 196 racemate 12 H H F H 1 239-240 −95.4 13 H H F H 1 239-240 (+)-form14 H H F H 2 222-223 racemate 15 H H F H 2 247-249 77.6 16 H H F H 2247-249 +79.6 17 H Cl H H 1 235-239 −81.6 18 H Cl H H 1 199-201 (+)-form19 H Cl H H 2 232 −46.7 20 H Cl H H 2 232-234 (+)-form

[0592] Trifluoromethyl Compounds TABLE 6

Com- Flash point Isomerism or pound R5 R6 R7 R8 n = [° C.] [α]_(D) 21 HH H H 1 205 racemate 22 H H H H 1 222-223 −96.5 23 H H H H 1 219-221(+)-form 24 H H H H 2 218-222 racemate 25 H H H H 2 220-221 −16.4 26 H HH H 2 220-222 (+)-form 27 H H H H 4 150-153 racemate 28 H H F H 1242-245 racemate 29 H H F H 1 235-246 −40.1 30 H H F H 1 244-246(+)-form 31 H H F H 2 241-244 racemate 32 H H F H 2 242-244 −82.7 33 H HF H 2 242-244 (+)-form

[0593] Fluorine Compounds TABLE 7

Com- Flash point Isomerism or pound R5 R6 R7 R8 n = [° C.] [α]_(D) 34 HH H H 1 215-216 racemate 35 H H H H 1 260-262 −113.3 36 H H H H 1260-263 (+)-form 37 H H H H 2 190-191 racemate 38 H H H H 2 198-201−103.4 39 H H H H 2 207-209 +103 40 H H H H 3 168-171 −117.6 41 H H H H3 167-170 +112.3 42 H H H H 4 90-93 racemate 43 H H H H 4 178-184 −10544 H H H H 4 185-187 +102.6 45 F H H H 1 230-232 racemate 46 F H H H 1238-250 −106.3 47 F H H H 1 254-256 (+)-form 48 F H H H 2 182-185racemate 49 H H F H 1 198-199 racemate 50 H H F H 1 240 −130.2 51 H H FH 1 241 (+)-form 52 F H F H 1 215 racemate 53 F H F H 2 205 racemate

[0594] Bromine Compounds TABLE 8

Com- Flash point Isomerism or pound R5 R6 R7 R8 n = [° C.] [α]_(D) 54 HH H H 1 196-200 racemate 55 H H H H 1 239-241 −56.6 56 H H H H 1 240-241+56.0

EXAMPLE 176-[2-Hydroxy-4-methyl-4-(3-methyl-2-nitrophenyl)-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0595] Precursors

2-Methyl-2-(3-methyl-2-nitrophenyl)-propionitrile

[0596] Analogously to the process that is described for2-(5-fluoro-2-methylphenyl)-2-methylpropionitrile,2-methyl-2-(3-methyl-2-nitrophenyl)-propionitrile is synthesized,boiling point 140° C./0.05 hPa.

2-Methyl-2-(3-methyl-2-nitrophenyl)-propionaldehyde

[0597] Analogously to the process that is described for2-(5-fluoro-2-methylphenyl)-2-methylpropionaldehyde,2-methyl-2-(3-methyl-2-nitrophenyl)-propionaldehyde, boiling point 140°C./0.05 hPa, is obtained.

4-Methyl-4-(3-methyl-2-nitrophenyl)-2-oxovaleric acid

[0598] Analogously to the process that is described for4-(5-fluoro-2-methylphenyl)-4-methyl-2-oxovaleric acid,4-methyl-4-(3-methyl-2-nitrophenyl)-2-oxovaleric acid is obtained as anoil.

[0599]6-[4-Methyl-4-(3-methyl-2-nitrophenyl)-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-oneis obtained analogously to5-[4-(5-fluoro-2-methylphenyl)-4-methyl-2-oxovaleroylamino]phthalidefrom 4-methyl-4-(3-methyl-2-nitrophenyl)-2-oxovaleric acid and6-amino-2,3-benzoxazin-1-one, flash point 184-187° C.

6-[2-Hydroxy-4-methyl-4-(3-methyl-2-nitrophenyl)-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one

[0600]

[0601] was obtained analogously to Example 1 from6-[4-methyl-4-(3-methyl-2-nitrophenyl)-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-one,flash point 201-203° C.

EXAMPLE 185-[4-(2-Amino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl-amino]-phthalide

[0602]

[0603] 65.8 mg(5-fluoro-2-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-phthalidein 15 ml of methanol is reduced at normal pressure within 3 hours in thepresence of 20 mg of palladium/carbon (10%) with hydrogen, suctioned offon diatomaceous earth and concentrated by evaporation. Afterrecrystallization from ethyl acetate/diisopropyl ether, 51 mg of5-[4-(2-amino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-phthalideof flash point 174° C. is obtained.

EXAMPLE 196-[4-(2-Amino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl-amino]-4-methyl-2,3-benzoxazin-1-one

[0604]

[0605] 42 mg of6-[4-(5-fluoro-2-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-oneis dissolved in 1 ml of acetic acid and 1 ml of tetrahydrofuran b, mixedwith 22.5 mg of iron powder and stirred for 16 hours at roomtemperature. It is suctioned off on diatomaceous earth, concentrated byevaporation, the residue is taken up in ethyl acetate and washed with asaturated sodium hydrogen carbon solution. After chromatography onsilica gel with hexane/ethyl acetate (1.5+1) and recrystallization fromdiisopropyl ether, 10 mg of6-[4-(2-amino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-oneis obtained, flash point 208° C.

EXAMPLE 206-[4-(2-Acetylamino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one

[0606]

[0607] 9.4 mg of6-[4-(2-amino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-oneand 0.04 ml of acetic acid anhydride in 0.5 ml of tetrahydrofuran arestirred for 2 days at room temperature, and mixed with ethyl acetate andsodium bicarbonate solution. The ethyl acetate solution is dried andconcentrated by evaporation. After chromatography on silica gel, 8 mg of6-[4-(2-acetylamino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-oneis obtained.

[0608] MS (ei): M⁽⁺⁾=510

EXAMPLE 215-[4-(2-Acetylamino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide

[0609]

[0610] is obtained analogously to Example 20 from5-[4-(2-amino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-phthalide,flash point 125° C.

EXAMPLE 225-[4-(5-Fluoro-2-mesylaminophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide

[0611]

[0612] 17.7 mg of5-[4-(2-amino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-phthalide,0.4 ml of pyridine and 0.078 ml of mesyl chloride are stirred for 17hours at room temperature, mixed with ethyl acetate, and washed threetimes with 1N hydrochloric acid. The ethyl acetate solution is dried andconcentrated by evaporation. After chromatography on silica gel withethyl acetate/hexane (1:1), 11 mg of5-[4-(5-fluoro-2-mesylaminophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl-amino]-phthalideis obtained, flash point 218° C.

EXAMPLE 23

[0613]6-[4-(2-Bromo-3-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-oneis obtained analogously to Example 3 from6-[4-(2-bromo-3-methoxyphenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-one,MS (esi): M⁽⁺⁾+1=543 (⁷⁹Br) and 545 (⁸¹Br)

[0614] Separation of the Enantiomers of Example 23

[0615] The enantiomer mixture of Example 23 is separated bychromatography on chiral support medium (CHIRALPAK AD®, DAICEL Company)with hexane/ethanol (93:7, vv). Thus obtained from 200 mg of racemateare:

[0616](−)-6-[4-(2-Bromo-3-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-oneas a first fraction: 86 mg, [flash point 233-235° C., α_(D)=−81.40°(c=0.5 in chloroform)] and

[0617](+)-6-[4-(2-Bromo-3-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-oneas a second fraction: 82 mg.

EXAMPLE 24(+)-6-[4-(2-Bromo-3-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one

[0618]

[0619] 78 mg of(+)-6-[4-(2-bromo-3-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-oneis mixed in 1.4 ml of dichloromethane at 0° C. with 0.71 ml of a 1 molarsolution of boron tribromide in dichloromethane. After 2 hours ofstirring at 0° C., the mixture is added to water, extracted with ethylacetate, the organic phase is dried (Na₂SO₄) and concentrated byevaporation. After the residue is triturated with hexane, the titlecompound is obtained in crystalline form, flash point 226-231° C.,[α]_(D)=+91.1° (c=0.5 in chloroform)

EXAMPLE 25(−)-6-[4-(2-Bromo-3-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one

[0620]

[0621] Example 25 is produced analogously to Example 24 starting formthe corresponding(−)-6-[4-(2-bromo-3-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one.Flash point 227-231° C., [α]_(D)=−94.3° (c=0.5 in chloroform).

EXAMPLE 266-[4-(2,3-Difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylcaproylamino]-4-methyl-2,3-benzoxazin-1-one

[0622] Precursors

2-Methyl-2-(2,3-difluorophenyl)butyronitrile and2-methyl-2-(2,6-difluorophenyl)butyronitrile

[0623]

[0624] A solution of 5.0 g (37.85 mmol) of 1,2,3-trifluorobenzene, 3.30g (39.74 mmol) of 2-methylbutylnitrile and 75.7 ml (0.5 M in toluene) ofpotassium-bis-trimethylsilylamide in 182 ml of toluene is heated for 3hours at 60° C. It is mixed with ice water and ether. The organic phaseis acidified with 10% H₂SO₄ and washed three times with water, dried(Na₂SO₄) and concentrated by evaporation in a vacuum. Afterchromatography on silica gel with 0-4% ether-hexane, 3.8 g of2-methyl-2-(2,3-difluorophenyl)butyronitrile and 1.6 g of2-methyl-2-(2,6-difluorophenyl)butyronitrile are obtained.

[0625] 2-Methyl-2-(2,3-difluorophenyl)butyronitrile:

[0626]¹H-NMR (CDCl₃), δ (ppm)=0.88 (t, 3H), 1.81 (s, 3H), 1.95-2.1 (m,1H), 2.1-2.25 (m, 1H), 7.05-7.2 (m, 2H), 7.3-7.4 (m, 1H).

[0627] 2-Methyl-2-(2,6-difluorophenyl)butyronitrile:

[0628]¹H-NMR (CDCl₃), δ (ppm)=1.06 (t, 3H), 1.89 (t, 3H), 1.95-2.1 (m,H), 2.15-2.3 (m, H), 6.85-6.95 (m, 2H), 7.2-7.3 (m, 1H).

2-(2,3-Difluorophenyl)-2-methylbutyraldehyde

[0629]

[0630] Analogously to the process that is described for2-(5-fluoro-2-methylphenyl)-2-methylpropionaldehyde,2-(2,3-difluorophenyl)-2-methylbutyronitrile is obtained as a colorlessoil.

[0631] 1H-NMR (CDCl₃), δ (ppm)=0.79 (t, 3H), 1.41 (s, 3H), 1.8 5-2.0 (m,1H), 2.0-2.15 (m, 1H), 7.0-7.3 (m, 3H), 9.68 (d, 1H).

4-(2,3-Difluorophenyl)-4-methyl-2-oxocaproic acid

[0632]

[0633] Analogously to the process that is described for4-(5-fluoro-2-methyphenyl)-4-methyl-2-oxovaleric acid,4-(2,3-difluorophenyl)-4-methyl-2-oxocaproic acid is obtained: ¹H-NMR(CDCl₃), δ (ppm)=0.71 (t, 3H), 1.47 (s, 3H), 1.7 (m, H), 2.0 (m, 1H),3.26 (d, 1H), 3.74 (d, 1H), 6.9-7.1 (m, 3H).

6-[4-(2,3-Difluorophenyl)-4-methyl-2-oxocaproylamino]-4-methyl-2,3-benzoxazin-1-one

[0634]

[0635] Analogously to the process that is described for6-[4-(5-fluoro-2-methylphenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-one,6-[4-(2,3-difluorophenyl)-4-methyl-2-oxocaproylamino]-4-methyl-2,3-benzoxazin-1-oneis obtained:

[0636]¹H-NMR (CDCl₃), δ (ppm)=0.73 (t, 3H), 1.5 (s, 3H), 1.7 (m, 1H),2.05 (m, 1H), 2.58 (s, 3H), 3.37 (d, 1H), 3.84 (d, 1H), 7.0 (m, 3H),7.72 (dd, 1H), 8.24 (d, 1H), 8.33 (d, 1H), 9.0 (bs, 1H).

6-[4-(2,3-Difluorophenyl)-2-hydroxy-4-methyl-4-trifluoromethylcaproylamino]-4-methyl-2,3-benzoxazin-1-one

[0637]

[0638] Analogously to the process that is described for6-[4-(5-fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one,6-[4-(2,3-difluorophenyl)-2-hydroxy-4-methyl-4-trifluoromethylcaproylamino]-4-methyl-2,3-benzoxazin-1-oneis obtained. The diastereomer mixture is separated by chromatography onsilica gel with 20-100% ethyl acetate/hexane.

[0639] Diastereomer 1: ¹H-NMR (CDCl₃), δ (ppm)=0.66 (t, 3H), 1.39 (s,3H), 1.7 (m, 1H), 2.1 (m, 1H), 2.61 (s, 3H), 2.7 (m, 2H), 6.9-7.2 (m,3H), 7.67 (dd, 1H), 8.31 (d, 1H), 8.37 (d, 1H), 8.8 (s, 1H)

[0640] Diastereomer 2: ¹H-NMR (CDCl₃), δ (ppm)=0.62 (t, 3H), 1.59 (s,3H), 1.6 (m, 1H), 2.15 (m, 1H), 2.23 (d, 1H), 2.55 (s, 3H), 3.07 (d,1H), 6.58 (m, 1H), 6.71 (m, 1H), 6.92 (m, 1H), 7.46 (dd, 1H), 8.01 (d,1H), 8.27 (d, 1h), 8.3 (s, 1H)

EXAMPLE 276-[4-(2,6-Difluorophenyl)-2-hydroxy-4-methyl-4-trifluoromethylcaproylamino]-4-methyl-2,3-benzoxazin-1-one

[0641] Precursors

2-(2,6-Difluorophenyl)-2-methylbutyraldehyde

[0642]

[0643] Analogously to the process that is described for2-(5-fluoro-2-methylphenyl)-2-methylpropionaldehyde,2-(2,6-difluorophenyl)-2-methylbutyronitrile is obtained as a colorlessoil.

[0644]¹H-NMR (CDCl₃), δ (ppm)=0.83 (t, 3H), 1.49 (t, 3H), 1.9-2.1 (m,2H), 6.85-6.95 (m, 2H), 7.2-7.3 (m, 1H), 9.69 (t, 1H).

4-(2,6-Difluorophenyl)-4-methyl-2-oxocaproic acid

[0645]

[0646] Analogously to the process that is described for4-(5-fluoro-2-methylphenyl)-4-methyl-2-oxovaleric acid,4-(2,6-difluorophenyl)-4-methyl-2-oxocaproic acid is obtained: ¹H-NMR(CDCl₃), δ (ppm)=0.76 (t, 3H), 1.62 (t, 3H), 1.7 (m, H), 1.9 (m, 1H) 3.0(dt, 1H), 4.0 (d, 1H), 6.8 (m, 2H), 7.13 (m, 1H).

6-[4-(2,6-Difluorophenyl)-4-methyl-2-oxocaproylamino]-4-methyl-2,3-benzoxazin-1-one

[0647]

[0648] Analogously to the process that is described for6-[4-(5-fluoro-2-methylphenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-one,6-[4-(2,6-difluorophenyl)-4-methyl-2-oxocaproylamino]-4-methyl-2,3-benzoxazin-1-oneis obtained:

[0649]¹H-NMR (CDCl₃), δ (ppm)=0.81 (t, 3H), 1.64 (t, 3H), 1.77 (m, 1H),1.96 (m, 1H), 2.5 (s, 3H), 3.12 (dt, 1H), 4.09 (d, 1H), -6.8 (m, 2H),7.15 (m, 1H), 7.77 (dd, 1H), 8.30 (d, 1H), 8.34 (d, 1H), 9.1 (bs, 1H).

6-[4-(2,6-Difluorophenyl)-2-hydroxy-4-methyl-4-trifluoromethylcaproylamino]-4-methyl-2,3-benzoxazin-1-one

[0650]

[0651] Analogously to the process that is described for6-[4-(5-fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one,6-[4-(2,6-difluorophenyl)-2-hydroxy-4-methyl-4-trifluoromethylcaproylamino]-4-methyl-2,3-benzoxazin-1-oneis obtained as a diastereomer mixture: ¹H-NMR (CDCl₃), δ (ppm)=0.7 (m,3H), 1.4 (m, 1H), 1.5, 1.7, (2t, 3H), 2.0-3.2 (m, 6H), 6.4-7.3 (m, 3H),7.4-8.4 (m, 3H), 8.5, 8.9 (2bs, 1H).

EXAMPLE 286-{3-[4-(2-Chloro-5-fluorophenyl)-tetrahydropyran-4-yl]-2-hydroxy-2-trifluoromethylpropionylamino}-4-methyl-2,3-benzoxazin-1-one

[0652] Precursors

4-(2-Chloro-5-fluorophenyl)-tetrahydropyran-4-carbonitrile

[0653] 6.76 g of (2-chloro-5-fluorophenyl)-acetonitrile and 5.7 ml of2,2-dichlorodiethyl ether are dissolved in 100 ml of dimethylformamideand mixed within 2.5 hours with 3.7 g of sodium hydride (60%) whilebeing cooled with ice. After 3 hours at 0° C. and 16 hours at roomtemperature, it is mixed with ice water and ethyl acetate, acidifiedwith 1 M hydrochloric acid, and the ethyl acetate phase is washed withwater, dried (Na₂SO₄) and concentrated by evaporation. Afterchromatography on silica gel, 6.2 g of4-(2-chloro-5-fluorophenyl)-4-pyranylcarbonitrile, flash point 91-93°C., is obtained.

4-(2-Chloro-5-fluorophenyl)-tetrahydropyran-4-carbaldehyde

[0654] Analogously to the process that is described for2-(5-fluoro-2-methylphenyl)-2-methylpropionaldehyde,4-(2-chloro-5-fluorophenyl)-tetrahydropyran-4-carbaldehyde is obtainedas a colorless oil, boiling point 145° C./0.04 hPa.

3-[4-(2-Chloro-5-fluorophenyl)-tetrahydropyran-4-yl]-2-oxopropionic acid

[0655] Analogously to the process that is described for4-(5-fluoro-2-methylphenyl)-4-methyl-oxavaleric acid,3-[4-(2-chloro-5-fluorophenyl)-tetrahydropyran-4-yl]-2-oxo-propionicacid is obtained, flash point 158° C.

6-{3-[4-(2-Chloro-5-fluorophenyl)-tetrahydropyran-4-yl]-2-oxopropionylamino}-4-methyl-2,3-benzoxazin-1-one

[0656] Analogously to the process that is described for6-[4-(5-fluoro-2-methylphenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-one,6-{3-[4-(2-chloro-5-fluorophenyl)-tetrahydropyran-4-yl]-2-oxopropionylamino}-4-methyl-2,3-benzoxazin-1-oneis synthesized. Flash point 206-208° C.

6-{3-[4-(2-Chloro-5-fluorophenyl)-tetrahydropyran-4-yl]-2-hydroxy-2-trifluoromethylpropionylamino}-4-methyl-2,3-benzoxazin-1-one

[0657]

[0658] Analogously to the process that is described for6-[4-(5-fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one,6-{3-[4-(2-chloro-5-fluorophenyl)-tetrahydropyran-4-yl]-2-hydroxy-2-trifluoro-methylpropionylamino}-4-methyl-2,3-benzoxazin-1-oneis synthesized. Flash point 224-226° C.

[0659] Separation of Enantiomers of Example 28

[0660] The enantiomer mixture of Example 28 is separated bychromatography on chiral support medium (CHIRALPAK AD®, DAICEL Company)with hexane/ethanol (9:1, vv). Thus obtained from 300 mg of racemateare:

[0661](−)-6-{3-[4-(2-Chloro-5-fluorophenyl)-tetrahydropyran-4-yl]-2-hydroxy-2-trifluoromethylpropionylamino}-4-methyl-2,3-benzoxazin-1-oneas a first fraction, 129 mg, flash point 181-183° C., [α_(D)=−83.20°(c=0.5 in tetrahydrofuran)] and

[0662](+)-6-{3-[4-(2-Chloro-5-fluorophenyl)-tetrahydropyran-4-yl]-2-hydroxy-2-trifluoromethylpropionylamino}-4-methyl-2,3-benzoxazin-1-oneas a second fraction, 129 mg, flash point 181-183° C.

EXAMPLE 29

[0663] In the glucocorticoid receptor-(GR)-binding test with use ofcytosol preparations of Sf9 cells that have been infected withrecombinant baculoviruses, which code for the GR, and with use of 10 nMof [³H]-dexamethasone as a reference substance, (cf. Lefebvre et al. J.Steroid Biochem., 33, 557-563, 1989), the compounds of formula 1 show ahigh to very high affinity to the GR (see Table 9). TABLE 9 GR-BindingTest** Compound IC₅₀ [mol/l] Example 38 <3.0 × 10⁻¹⁰ Example 16,compound 26   1.6 × 10⁻⁸ Example 16, compound 33   1.1 × 10⁻⁹ Example 3,compound 9 <3.0 × 10⁻¹⁰ Example 16, compound 16   6.2 × 10⁻¹⁰ Example16, compound 13 <3.0 × 10⁻¹⁰ Dexamethasone   2.8 × 10⁻⁸ Prednisolone  4.0 × 10⁻⁸

EXAMPLE 30

[0664] The potency of the antiinflammatory action is determined in acell test by the inhibition of the secretion of cytokine IL-8. Thecompounds of general formula I according to the invention inhibit thesecretion of cytokine IL-8 in the human monocyte cell line THP-1 that istriggered by lipopolysaccharide (LPS). The concentration of thecytokines was determined in the supernatant by means of commerciallyavailable ELISA kits. In this connection, the compounds of formula 1show a high to very high potency and action in inhibition (see Table10). TABLE 10 IL-8 Values Inhibition of IL-8 Secretion Inhibition ofIL-8 Secretion Compounds IC50 [mol/l] Effectiveness [%] Example 38 8.6 ×10⁻⁹ 56 Example 16, 4.3 × 10⁻⁹ 77 compound 26 Example 16, 3.0 × 10⁻⁸ 45compound 33 Example 3, 6.5 × 10⁻⁸ 51 compound 9 Example 16, 1.0 × 10⁻⁸80 compound 16 Example 16, 9.6 × 10⁻⁹ 58 compound 13 Prednisolone 2.4 ×10⁻⁸ 95

EXAMPLE 31

[0665] The antiinflammatory actions of the compounds of general formulaI were tested in the animal experiment in the croton oil-inducedinflammation in rats and mice (J. Exp. Med. (1995), 182, 99-108). Inthis respect, croton oil in an ethanolic solution was administeredtopically to the ears in the animals. The test substances weresystemically administered two hours before the croton oil. After 16-24hours, the ear weight was measured as a yardstick of the inflammatoryedema. In this connection, the compounds of general formula I show aninhibition of the croton-oil-induced inflammation that is comparable tothe standard (prednisolone) and is sometimes also stronger (see Table11). TABLE 11 Inhibition of Edema Formation Edema inhibition [%] Edemainhibition [%] Compounds with 3 mg/kg with 30 mg/kg Example 38 58 101Example 16, 11 81 compound 26 Example 16, 77 86 compound 33 Example 3,50 92 compound 9 Example 16, 54 78 compound 16 Example 16, 47 106compound 13 Prednisolone 35 84

EXAMPLE 32

[0666] As a parameter for the side effects of the steroid-inducedcatabolic metabolism, the activity of the enzyme tyrosinaminotransferase (TAT) was determined from liver homogenates by photometry.The activity represents a good yardstick of the undesirable metabolicactions of the glucocorticoids. To measure the TAT induction, theanimals are sacrificed 8 hours after the test substances areadministered, the livers are removed, and the TAT activity in thehomogenate is measured. In this test, at doses at which they have anantiinflammatory action, the compounds of general formula I inducelittle or no tyrosinamino transferase in comparison to the steroids(Table 12). TABLE 12 Induction of the Tyrosinamino Transferase ActivityInduction factor* Induction factor* for Compounds for TAT with 3 mg/kgTAT with 30 mg/kg Example 38 1.2 6.0 Example 16, 1.4 3.7 compound 26Example 16, 1.3 2.0 compound 16 Prednisolone 2.6 8.0

1. Use of the compounds of general formula I

in which R¹ and R² are the same or different and stand for a hydrogenatom, a C₁-C₅ alkyl group, or, together with the C-atom of the chain,stand for a ring with a total of 3-7 links, R³ stands for astraight-chain or branched C₁-C₅ alkyl group or a straight-chain orbranched, partially or completely fluorinated C₁-C₅ alkyl group, Astands for the group

 (the dashed line means the interface site), in which R⁴ to R⁸ are thesame or different from one another and mean a hydrogen atom, a halogenatom, a cyano group, a nitro group, a COOR⁹ group whereby R⁹ stands fora hydrogen atom, a straight-chain or branched C₁-C₅ alkyl group or abenzyl group, a CONR¹⁰ group, whereby R¹⁰ stands for a hydrogen atom ora straight-chain or branched C₁-C₅ alkyl group, an NHR¹¹ group, wherebyR¹¹ stands for a hydrogen atom, a straight-chain or branched C₁-C₅ alkylgroup, a straight-chain or branched, partially or completely fluorinatedC₁-C₅ alkyl group, a C₁-C₅ acyl group, an —SO₂—(C₁-C₅) alkyl group or an—SO₂-phenyl group that is optionally substituted by halogen or a C₁-C₅alkyl group, a straight-chain or branched C₁-C₅ alkyl group, astraight-chain or branched C₂-C₅ alkenyl group, a straight-chain orbranched C₂-C₅ alkinyl group, a straight-chain or branched C₁-C₅ alkylgroup that is partially or completely substituted by fluorine atoms, aC₁-C₅ acyl group, an aryl radical or a heteroaryl radical, or R⁴ and R⁵together with the two carbon atoms of ring A mean a saturated orunsaturated carbocyclic ring with a total of 5-7 links, Ar stands for aring system, selected from the group of general partial formula 1 or 2,

 in which radicals X^(3a), X^(3b), X⁴, X⁶, X⁷ (in partial formula 1) andY⁴, Y⁵, Y⁷, and Y⁸ (in partial formula 2) are the same or different andmean a hydrogen atom, a straight-chain or branched C₁-C₅ alkyl group, ora straight-chain or branched, partially or completely fluorinated C₁-C₅alkyl group, radicals X⁴, X⁶, X⁷ (in partial formula 1) or Y⁵, Y⁷, Y⁸(in partial formula 2) in addition are the same or different and mean ahydrogen atom, a halogen atom, a hydroxy group, a C₁-C₅ alkoxy group ora C₁-C₅ alkanoyloxy group, as well as their racemates or separatelypresent stereoisomers, and optionally their physiologically compatiblesalts for the production of a pharmaceutical agent for treatinginflammations.
 2. Compounds of general formula I according to claim 16-[4-(5-Fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one5-[4-(5-fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-phthalide6-[4-(2-chloro-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one5-[4-(5-fluoro-2-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-phthalide6-[4-(5-fluoro-2-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one5-[4-(3-fluoro-4-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-phthalide6-[4-(3-fluoro-4-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one6-[4-(2-bromo-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one6-[4-(indan-4′-yl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one(−)6-[4-(indan-4′-yl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one(+)6-[4-(indan-4′-yl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one6-[4-(5-fluoro-2-vinylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one (−)6-[4-(5-fluoro-2-vinylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one(+)6-[4-(5-fluoro-2-vinylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one6-[2-hydroxy-4-methyl-2-trifluoromethyl-4-(4-trifluoromethylphenyl)-valeroylamino]-4-methyl-2,3-benzoxazin-1-one(−)6-[2-hydroxy-4-methyl-2-trifluoromethyl-4-(4-trifluoromethylphenyl)-valeroylamino]-4-methyl-2,3-benzoxazin-1-one(+)6-[2-hydroxy-4-methyl-2-trifluoromethyl-4-(4-trifluoromethylphenyl)-valeroylamino]-4-methyl-2,3-benzoxazin-1-one6-[4-(2-bromo-3,5-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one(−)6-[4-(2-bromo-3,5-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one(+)6-[4-(2-bromo-3,5-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one6-[4-(3,5-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one (−)6-[4-(3,5-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one(+)6-[4-(3,5-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one6-[4-(2-cyano-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one6-[4-(2-ethenyl-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one6-[4-(2-ethyl-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one6-[4-(5-fluoro-2-phenylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one6-[4-{5-fluoro-2-(furan-2′-yl)phenyl}-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one6-[4-(2-bromo-3,5-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one6-[2-hydroxy-4-methyl-2-trifluoromethyl-4-(1-naphthyl)-valeroylamino]-4-methyl-2,3-benzoxazin-1-one(−)6-[2-hydroxy-4-methyl-2-trifluoromethyl-4-(1-naphthyl)-valeroylamino]-4-methyl-2,3-benzoxazin-1-one(+)6-[2-hydroxy-4-methyl-2-trifluoromethyl-4-(1-naphthyl)-valeroylamino]-4-methyl-2,3-benzoxazin-1-one6-[4-(2-chlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one(−)-6-[4-(2-chlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one(+)-6-[4-(2-chlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one6-[4-(2-chloro-3-fluoro-phenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one(−)-6-[4-(2-chloro-3-fluoro-phenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one(+)-6-[4-(2-chloro-3-fluoro-phenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one6-[4-(2-chloro-4-fluoro-phenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one(−)-6-[4-(2-chloro-4-fluoro-phenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one(+)-6-[4-(2-chloro-4-fluoro-phenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one6-[4-(2-chloro-6-fluoro-phenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one(−)-6-[4-(2-chloro-6-fluoro-phenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one(+)-6-[4-(2-chloro-6-fluoro-phenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one6-[4-(2,3-dichlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one(−)-6-[4-(2,3-dichlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one(+)-6-[4-(2,3-dichlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one6-[4-(2,4-dichlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one(−)-6-[4-(2,4-dichlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one(+)-6-[4-(2,4-dichlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one6-[4-(2,5-dichlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one(−)-6-[4-(2,5-dichlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one(+)-6-[4-(2,5-dichlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one6-[4-(4-bromo-2-chlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one(−)-6-[4-(4-bromo-2-chlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one(+)-6-[4-(4-bromo-2-chlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one6-[4-(2-chloro-3-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one(−)-6-[4-(2-chloro-3-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one(+)-6-[4-(2-chloro-3-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one6-[4-(2-chloro-3-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one(−)-6-[4-(2-chloro-3-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one(+)-6-[4-(2-chloro-3-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one6-[4-(2-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one(−)-6-[4-(2-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one(+)-6-[4-(2-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one6-[4-(2,3-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one(−)-6-[4-(2,3-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one(+)-6-[4-(2,3-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one(−)-6-[4-(2,3-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylhexanoylamino]-4-methyl-2,3-benzoxazin-1-one(+)-6-[4-(2,3-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylhexanoylamino]-4-methyl-2,3-benzoxazin-1-one6-[4-(2,4-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one(−)-6-[4-(2,4-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one(+)-6-[4-(2,4-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one6-[4-(2,5-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one(−)-6-[4-(2,5-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one(+)-6-[4-(2,5-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one6-[4-(2,6-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one(−)-6-[4-(2,6-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one(+)-6-[4-(2,6-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one6-[4-(2,3,5-trifluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one(−)-6-[4-(2,3,5-trifluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one(+)-6-[4-(2,3,5-trifluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one6-[4-(2,3,4-trifluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one(−)-6-[4-(2,3,4-trifluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one(+)-6-[4-(2,3,4-trifluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one6-[4-(3-chloro-2-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one(−)-6-[4-(3-chloro-2-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl-amino]-4-methyl-2,3-benzoxazin-1-one(+)-6-[4-(3-chloro-2-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one6-[4-(4-chloro-2-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one(−)-6-[4-(4-chloro-2-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl-amino]-4-methyl-2,3-benzoxazin-1-one(+)-6-[4-(4-chloro-2-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl-amino]-4-methyl-2,3-benzoxazin-1-one6-[4-(2-fluoro-3-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one(−)6-[4-(2-fluoro-3-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl-amino]-4-methyl-2,3-benzoxazin-1-one(+)6-[4-(2-fluoro-3-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one6-[4-(2-bromophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one(−)-6-[4-(2-bromophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one(+)-6-[4-(2-bromophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one6-[4-(2-trifluoromethyl-phenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one(−)-6-[4-(2-trifluoromethyl-phenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one(+)-6-[4-(2-trifluoromethyl-phenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one6-[4-(4-fluoro-2-trifluoromethyl-phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroyl]-amino-4-methyl-2,3-benzoxazin-1-one(−)-6-[4-(4-fluoro-2-trifluoromethyl-phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroyl]-amino-4-methyl-2,3-benzoxazin-1-one(+)-6-[4-(4-fluoro-2-trifluoromethyl-phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroyl]-amino-4-methyl-2,3-benzoxazin-1-one6-[4-(5-fluoro-2-trifluoromethyl-phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroyl]-amino-4-methyl-2,3-benzoxazin-1-one(−)-6-[4-(5-fluoro-2-trifluoromethyl-phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroyl]-amino-4-methyl-2,3-benzoxazin-1-one(+)-6-[4-(5-fluoro-2-trifluoromethyl-phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroyl]-amino-4-methyl-2,3-benzoxazin-1-one6-[4-(5-chloro-2-trifluoromethyl-phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroyl]-amino-4-methyl-2,3-benzoxazin-1-one(−)-6-[4-(5-chloro-2-trifluoromethyl-phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroyl]-amino-4-methyl-2,3-benzoxazin-1-one(+)-6-[4-(5-chloro-2-trifluoromethyl-phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroyl]-amino-4-methyl-2,3-benzoxazin-1-one6-[3-{1-(2-chlorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one(−)6-[3-{1-(2-chlorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one(+)6-[3-{1-(2-chlorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one6-[3-{1-(2-chlorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one(−)-6-[3-(1-(2-chlorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one(+)-6-[3-{1-(2-chlorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one6-[3-{1-(2-chlorophenyl)-cyclopentyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one(−)-6-[3-{1-(2-chlorophenyl)-cyclopentyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one(+)-6-[3-{1-(2-chlorophenyl)-cyclopentyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one6-[3-{1-(2-chloro-4-fluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one(−)-6-[3-{1-(2-chloro-4-fluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethyl-propionyl]-amino-4-methyl-2,3-benzoxazin-1-one(+)-6-[3-{1-(2-chloro-4-fluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethyl-propionyl]-amino-4-methyl-2,3-benzoxazin-1-one6-[3-{1-(2-chloro-4-fluorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one(−)-6-[3-{1-(2-chloro-4-fluorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethyl-propionyl]-amino-4-methyl-2,3-benzoxazin-1-one(+)-6-[3-{1-(2-chloro-4-fluorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethyl-propionyl]-amino-4-methyl-2,3-benzoxazin-1-one6-[3-{1-(2-chloro-5-fluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one(−)-6-[3-{1-(2-chloro-5-fluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one(+)-6-[3-{1-(2-chloro-5-fluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethyl-propionyl]-amino-4-methyl-2,3-benzoxazin-1-one6-[3-{1-(2-chloro-5-fluorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one(−)-6-[3-{1-(2-chloro-5-fluorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethyl-propionyl]-amino-4-methyl-2,3-benzoxazin-1-one(+)-6-[3-{1-(2-chloro-5-fluorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethyl-propionyl]-amino-4-methyl-2,3-benzoxazin-1-one6-[3-{1-(2,4-dichlorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one(−)-6-[3-{1(2,4-dichlorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one(+)-6-[3-{1-(2,4-dichlorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one6-[3-{1-(2,4-dichlorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one(−)-6-[3-{1-(2,4-dichlorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one(+)-6-[3-{1-(2,4-dichlorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one6-[3-{1-(2-trifluoromethyl-phenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one(−)-6-[3-{1-(2-trifluoromethyl-phenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one(+)-6-[3-{1-(2-trifluoromethyl-phenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one6-[3-{1-(2-trifluoromethyl-phenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one(−)-6-[3-{1-(2-trifluoromethyl-phenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one(+)-6-[3-{1-(2-trifluoromethyl-phenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one6-[3-{1-(2-trifluoromethyl-phenyl)-cyclohexyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one(−)6-[3-{1-(2-trifluoromethyl-phenyl)-cyclohexyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one(+)6-[3-{1-(2-trifluoromethyl-phenyl)-cyclohexyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one6-[3-{1-(5-fluoro-2-trifluoromethyl-phenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one(−)-6-[3-{1-(5-fluoro-2-trifluoromethyl-phenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one(+)-6-[3-{1-(5-fluoro-2-trifluoromethyl-phenyl)-cyclopropyl}-2-hydroxy-2-trifluromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one6-[3-{1-(5-fluoro-2-trifluoromethyl-phenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one(−)-6-[3-{1-(5-fluoro-2-trifluoromethyl-phenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one(+)-6-[3-{1-(5-fluoro-2-trifluoromethyl-phenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one6-[3-{1-(2-fluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one(−)-6-[3-{1-(2-fluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one(+)-6-[3-{1-(2-fluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one6-[3-{1-(2-fluorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one(−)-6-[3-{1-(2-fluorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one(+)-6-[3-{1-(2-fluorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one6-[3-{1-(2-fluorophenyl)-cyclopentyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one(−)-6-[3-{1-(2-fluorophenyl)-cyclopentyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one(+)-6-[3-{1-(2-fluorophenyl)-cyclopentyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one6-[3-{1-(2-fluorophenyl)-cyclohexyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one(−)-6-[3-{1-(2-fluorophenyl)-cyclohexyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one(+)-6-[3-{1-(2-fluorophenyl)-cyclohexyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one6-[3-{1-(2,3-difluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one(−)-6-[3-{1-(2,3-difluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one(+)-6-[3-{1-(2,3-difluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl-amino]-4-methyl-2,3-benzoxazin-1-one6-[3-{1-(2,3-difluorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one(−)6-[3-{1-(2,3-difluorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one(+)6-[3-{1-(2,3-difluorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one6-[3-{1-(2,5-difluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one(−)-6-[3-{1-(2,5-difluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one(+)-6-[3-{1-(2,5-difluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one6-[3-{1-(2,3,5-trifluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one(−)-6-[3-{1-(2,3,5-trifluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one(+)-6-[3-{1-(2,3,5-trifluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl-amino]-4-methyl-2,3-benzoxazin-1-one6-[3-{1-(2,3,5-trifluorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one(−)-6-[3-{1-(2,3,5-trifluorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one(+)-6-[3-{1-(2,3,5-trifluorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl-amino]-4-methyl-2,3-benzoxazin-1-one6-[3-{1-(2-bromophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one(−)-6-[3-{1-(2-bromophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one(+)-6-[3-{1-(2-bromophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one6-[2-hydroxy-4-methyl-4-(3-methyl-2-nitrophenyl)-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one(−)6-[2-hydroxy-4-methyl-4-(3-methyl-2-nitrophenyl)-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one(+)6-[2-hydroxy-4-methyl-4-(3-methyl-2-nitrophenyl)-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one5-[4-(2-amino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl-amino]-phthalide(−)5-[4-(2-amino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl-amino]-phthalide(+)5-[4-(2-amino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl-amino]-phthalide6-[4-(2-amino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl-amino]-4-methyl-2,3-benzoxazin-1-one(−)6-[4-(2-amino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl-amino]-4-methyl-2,3-benzoxazin-1-one(+)6-[4-(2-amino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one6-[4-(2-acetylamino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one(−)6-[4-(2-acetylamino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one(+)6-[4-(2-acetylamino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one5-[4-(2-acetylamino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide(−)5-[4-(2-acetylamino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide(+)5-[4-(2-acetylamino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide5-[4-(5-fluoro-2-mesylaminophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide(−)5-[4-(5-fluoro-2-mesylaminophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide(+)5-[4-(5-fluoro-2-mesylaminophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide6-[4-(2-bromo-3-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one(−)6-[4-(2-bromo-3-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one(+)6-[4-(2-bromo-3-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one6-[4-(2-bromo-3-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one(−)6-[4-(2-bromo-3-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one(+)6-[4-(2-bromo-3-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one6-[4-(2-bromo-3-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one(−)-6-[4-(2-bromo-3-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one(+)-6-[4-(2-bromo-3-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one6-[4-(2,3-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylcaproylamino]-4-methyl-2,3-benzoxazin-1-one(−)6-[4-(2,3-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylcaproylamino]-4-methyl-2,3-benzoxazin-1-one(+)6-[4-(2,3-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylcaproylamino]-4-methyl-2,3-benzoxazin-1-one6-[4-(2,6-difluorophenyl)-2-hydroxy-4-methyl-4-trifluoromethylcaproylamino]-4-methyl-2,3-benzoxazin-1-one(−)6-[4-(2,6-difluorophenyl)-2-hydroxy-4-methyl-4-trifluoromethylcaproylamino]-4-methyl-2,3-benzoxazin-1-one(+)6-[4-(2,6-difluorophenyl)-2-hydroxy-4-methyl-4-trifluoromethylcaproylamino]-4-methyl-2,3-benzoxazin-1-one6-{3-[4-(2-chloro-5-fluorophenyl)-tetrahydropyran-4-yl]-2-hydroxy-2-trifluoromethylpropionylamino}-4-methyl-2,3-benzoxazin-1-one(−)6-{3-[4-(2-chloro-5-fluorophenyl)-tetrahydropyran-4-yl]-2-hydroxy-2-trifluoromethylpropionylamino}-4-methyl-2,3-benzoxazin-1-one(+)6-{3-[4-(2-chloro-5-fluorophenyl)-tetrahydropyran-4-yl]-2-hydroxy-2-trifluoromethylpropionylamino}-4-methyl-2,3-benzoxazin-1-one.3. 2,3-Benzoxazin-1-ones according to claim
 2. 4. Use of the compoundsof general formula I according to claim 2 for the production ofpharmaceutical agents.
 5. Use of the compounds according to claim 2 forthe production of a pharmaceutical agent for treating inflammations. 6.Pharmaceutical preparations that contain at least one compound accordingto claim 2 as well as pharmaceutically compatible vehicles.
 7. Use of atleast one compound of general formula I according to claim 1 for theproduction of pharmaceutical agents for treating at least one of thediseases that for the most part coincide with inflammatory, allergicand/or proliferative processes: (i) Lung diseases (ii) Rheumaticdiseases/auto-immune diseases/degenerative joint diseases (iii)Allergies (iv) Vascular diseases (vasculitis) (v) Dermatologicaldiseases (vi) Nephropathies (vii) Liver diseases (viii) Gastrointestinaldiseases (ix) Proctological diseases (x) Eye diseases (xi) Diseases ofthe ear-nose-throat area (xii) Neurological diseases (xiii) Blooddiseases (xiv) Tumor diseases (xv) Endocrine diseases (xvi) Transplants(xvii) Severe shock conditions (xviii) Substitution therapy withsuprarenal insufficiency (xix) Vomiting (xx) Pain with inflammatoryorigins (e.g., lumbago)